In 337, just before the death of Constantine the Great, Shapur II, provoked by the Roman rulers' backing of Roman Armenia, broke the peace concluded in 297 between emperors Narseh and Diocletian, which had been observed for forty years. This was the beginning of two long drawn-out wars (337–350 and 358-363) which were inadequately recorded.

After crushing a rebellion in the south, Shapur II invaded Roman Mesopotamia and captured Armenia. Apparently, nine major battles were fought. The most renowned was the inconclusive Battle of Singara (modern Sinjar, Iraq) in which Constantius II was at first successful, capturing the Persian camp, only to be driven out by a surprise night attack after Shapur had rallied his troops. The most notable feature of this war was the consistently successful defence of the Roman fortress city of Nisibis in Mesopotamia. Shapur besieged the city thrice (in 338, 346, 350 CE), and was repulsed each time.

Although victorious in battle, Shapur II could make no further progress with Nisibis un-taken. At the same time he was attacked in the east by Scythian Massagetae and other Central Asia nomads. He had to break off the war with the Romans and arrange a hasty truce in order to pay attention to the east. Roughly around this time the Hunnic tribes, most likely the Kidarites, whose king was Grumbates, make an appearance as an encroaching threat upon Sasanian territory as well as a menace to the Gupta Empire. After a prolonged struggle (353–358) they were forced to conclude a peace, and Grumbates agreed to enlist his light cavalrymen into the Persian army and accompany Shapur II in renewed war against the Romans, particularly participating in the Siege of Amida in 359.