Hitching in and around
There is a toll station Niš - Nais, just before Niš, if you're coming down south from direction of Belgrade using the motorway. There you can get rides straight to Sofia, or rides south towards Skopje and further on towards Greece, without entering into the city.
Take a city bus from the central square to Niška Banja (a one-way ticket should cost around 50 RSD, which is about 0.50€, conductors will charge it once you get on the bus). Get off the bus on the second-to-last stop, i.e. the stop right after the bus crosses over the railroad tracks, after about a 15 minutes journey. There is a roundabout and you can thumb after the roundabout. Here, you may catch 70% of all locals driving out of the city to your direction.
However, from this point you can walk 3.5 km further to reach an ideal hitchhiking position in the village of Prosek (Просек), where this road joins the highway and all the other traffic going towards Bulgaria. After 3 km down the road, you will notice a small junction where roads merge, and after some 400-500 m more, you will be standing in the right spot with a couple of well-frequented Turkish restaurants around and some roadside parking area for long-distance trucks (most of them again being Turkish). Although it is possible to get a ride at the previous spot, this one in Prosek (Просек) should be your goal for international rides, as you have excellent chances to find a straight ride to Bulgaria or even further towards Turkey.
Alternative and possibly easier way to get to Prosek hitchhiking point is to get one of those suburban buses that go around local villages. Get to the main bus station just around the fortress, don't enter main terminals but find a smaller one with only one ticket selling booth (looks like a bus stop with buses constantly flowing through, just by the street, and not by fortress walls), and get on a bus to village of Prosek (Просек). Ticket should not be more than 1.25€, and these buses depart at every 60 minutes or so. Ask driver to let you know where to get off as this is still a local suburban bus line and stops aren't well marked. Anyway, bus stop where you're getting off has a restaurant meters away with big neon STOP sign, so you can't miss it. Once you get off, walk some 100 meters backwards and there you are, right at the position described above.
North towards Belgrade
There are several possibilities.
From the main bus station walk straight along the "Bulevar 12. Februar" blvd after 3-4km you will get on the highway, but a good place to hitchhike is just before the highway, you will pass under an overpass few hundred meters after there will be a turn right for "Aleksinac" hitchhike after it, get a ride at lest to the Pay Toll name "Nais", using a sign with "NAIS" written on it is advisable. From the Pay toll you can hitchhike directly north to Belgrade or cross the highway and hitchhike south towards Skopje or Thessaloniki.
It is possible to get from the "Aleksinac" turn described above to the Nais tolls on foot (it may also be possible to get a short lift). Approximately 6 kilometres up the Aleksinac road, you can walk west through a village and then some fields to reach the motorway. Once you reach the motorway, you'll find the hotel Nais, a petrol station just beyond it with truck parking and then the toll area itself.
Next to the main bus station there's a suburban buses terminal and a bus stop on 'Bulevar 12. Februar' street, with "Branković" bakery being right across the street from the bus stop (adding this info for easier orientation). Get on a bus(bus ticket is 50 dinars(Feb.2013),although if you play dumb you can pass without paying), to Donji Komren (number 12 or 12s), and get off at the last stop. Continue walking that way and after few hundred meters, passing by petrol station on your right and under a motorway overpass, you should walk a few hundred meters past the overpass, there should be a turn towards Aleksinac, hitchhike just after it, preferably with a sign NAIS, it may take a while but, get a ride at least to the Nais toll area (naplatna rampa Niš) where you can then stand with a sign for your destination. All cars have to stop to get a ticket, it usually takes from 5-10min to get a ride to Belgrade.
If you are going straight to Belgrade accept only direct rides, since a lot of cars are going there and it's the biggest pay toll on the way.
Take bus no.10 ("9. maj") from the central square (the bus stop is next to McDonalds). Get off at the last stop, in a suburban area called Novo Selo (also referenced as "Naselje 9. maj"). The bus ride should cost around 50 RSD. Walk straight on in the same direction and cross a bridge over the motorway. You will come to a roundabout, and the left path leads to the motorway, heading south. You can hitch from here. The E80 and E75 split shortly afterwards, so make sure you're going in the right direction. For Skopje, Leskovac is on the way, so you can accept a ride to that vicinity.
Another possibility is to take the train towards Doljevac from the main railway station. Get out at Doljevac station (10 -15 minutes ride, ticket price 64 RSD, about 30 RSD if you manage to bribe the conductor), and take a 10 minutes walk to the motorway toll station (accros the fields).
For Kosovo: After passing town of Prokuplje, number of vehicles is getting somewhat lower. You're better taking a lift from vehicles registered to a foreign plates, as not many Serbian registered vehicles cross into Kosovo at all. A considerable number of trucks going into Kosovo also pass here.
What is important to notice here is the traffic structure on this particular road. Serbian vehicles are in most cases heading not further than town of Kuršumlija and nearby villages. These that pass Kuršumlija in most cases head to Prolom Banja (mineral springs health resort site) or Đavolja Varoš/Devil's Town, natural rock formations site that is a tourist hot-spot nowdays. Both of these are pretty much off the main road. These vehicles going to the border with Kosovo (Merdare village) and further, are very low in numbers.
Therefore, have in mind that if you catch a ride that heads to some of these previously mentioned sites, you may easily get stuck on the road at these last 10 or 15 kilometers before Merdare/Kosovo checkpoint, without much traffic at all.
Depending where your location is, you need to catch bus no.2 (also labeled as "Bubanj - Donja Vrežina"), towards Donja Vrežina neighborhood. The bus ride should cost about 50 RSD. Bus stop where you shall get off the bus is the one before the last stop. You will easily recognize it by suburban atmosphere and lots of light industry storage facilities right across the bus stop. Once you're there, you can start hitchhiking, as visibility is very good at that point and the road is straight for about a kilometer. Have in mind that international and transit traffic, and good percent of locals use motorway rather than this road. However, some general experiences are that about 50% of the locals going into your way are passing here. For the other half of a local traffic, you would have to hitch on the motorway, and it's not too easy to get on the city/motorway intersection for this route by public transport.
Once you hitch a ride, if the driver doesn't go all the way you need, it is recommendable to get out of the car some 8 km away at the motorway intersection near the village of Malcha. Vehicles must pass there, and there's no other intersection road, so you can't miss the place. Once you get there, thumb. You are catching almost 100% of traffic going toward Zajechar and further, and visibility is good.