Niš has been a crossroads for as long as there have been roads. The Roman highway from Belgrade to Constantinople ran through it, and so did every army that wanted one or the other. The Romans called it Naissus, and around 272 AD a boy called Constantine was born here, the first Christian emperor, who would move the capital of the empire to the Bosphorus. Attila's Huns sacked it in the 440s; later it changed hands between Byzantium, Bulgaria and Serbia, and in 1189 the Serbian ruler Stefan Nemanja met the German emperor Frederick Barbarossa here on his way to the Third Crusade. The Ottomans took Niš in 1386 and, apart from two short Austrian occupations, held it until the Serbian army entered in January 1878. In 1914-15 it was briefly Serbia's wartime capital.
You can see most of that in a short walk: an Ottoman fortress on the river with a Roman street inside, Roman mosaics a few kilometers east, a tower the Ottomans built from the skulls of Serbian rebels, and a Nazi camp that some of its prisoners escaped in one of the bravest breakouts of the war. Niš is also the start of the Serbian south, and you'll hear it straight away: people speak a dialect the rest of the country loves to imitate, eat burek for breakfast, and take their grilled meat very seriously.
The city itself fills three days, and the region around it is the reason to stay for five. Day one is the fortress and the center, day two the Skull Tower, Mediana and the spa at Niška Banja, day three the 20th century and the market, day four a drive through the Sićevo gorge to Pirot, and day five Prokuplje and the earth pillars of Devil's Town. Start on a Tuesday: every site of the National Museum is closed on Mondays. For the rest of the country, see Serbia and the Belgrade guide.