In 1185 the bolyari Petâr and Asen led a successful popular uprising against Byzantium, proclaiming the Second Kingdom in Veliko Târnovo, henceforth its capital. Byzantine forces under Emperor Isaac Angelus confidently expected to be able to crush the rebel state at birth, but after two attempts in 1187 and 1190, were finally forced to accept Bulgarian independence. Asen's brother and successor Tsar Kaloyan (1197-1207) extended Bulgaria's borders further, recapturing Varna and parts of Macedonia and Thrace from Byzantium. However, it was the fall of Constantinople to the Crusaders in 1204 that gave the Second Kingdom the chance it needed to consolidate and grow. Exiled Byzantine aristocrats, having established statelets in Epirus and Nicaea, proceeded to make war on both each other and the Crusaders' self-styled Latin Empire of the East . Tsar Kaloyan sought to exploit this fragmentation of Byzantine power in the Balkans, dreaming of one day setting up a Slav-Greek empire of his own.

Kaloyan succesfully negotiated union with the Catholic church in 1204 in the hope that the pope would support Bulgarian expansion, although at grass-roots level Bulgaria's church remained Orthodox in all but name. Widely admired in his own time (the name Kaloyan was derived from the Greek for "John the Handsome"), Kaloyan was also mercilessly cruel, notoriously razing Plovdiv to the ground and flaying its leading citizens alive in 1205, and hostile chroniclers were subsequently to dub him Skiloyan - "John the Dog".

Kaloyan inflicted a stunning defeat on the Latin rulers of Constantinople in 1205, capturing Emperor Baldwin and holding him prisoner in Târnovo. Before he could take advantage of this success, however, Kaloyan was murdered in a palace coup - as were almost all of Bulgaria's thirteenth-century tsars. A period of anarchy ensued under Tsar Boril before Ivan Asen II (1218-41) could restore order and continue the expansion of Bulgaria's frontiers. His victory over Theodore Comnenus of Epirus at Klokotnitsa in 1230 won him territories from the Adriatic to the Aegean, and ushered in an era of prestige and prosperity that marks the zenith of medieval Bulgaria's development. Ivan Asen also brought an end to the union with Rome, allowing a vibrantly Orthodox, Bulgaro-Byzantine culture to flourish.