In 1547, a newly crowned Ivan IV, "the Terrible" (r. 1533–84), ordered the seizure of Kazan, capital of the Turkic Khanate of Kazan, founded in the 15th century and one of the successor states of the Mongol Golden Horde. Strategically located 450 miles east of Moscow on the Volga River, Kazan was attacked for two principal reasons. First, the Khanate had launched disruptive and destructive assaults on Moscow and the territories of the tsardom, sacking towns and taking tens of thousands of prisoners. Second, Kazan stood between Muscovy and its ambition to exploit the resources of the vast Siberian lands beyond the Ural Mountains.

Bad weather and stubborn resistance had prevented Ivan's army from taking the city during his first campaign, so in 1552 Ivan set out again on a mission to conquer Kazan, spurred by rising suspicions at home that his previous defeat meant that God held the young, inexperienced tsar in contempt. Towns along the right bank of the Volga River swore loyalty to Ivan, who honored a new saint at each stop. Ivan's army took Kazan after placing mines in underground dugouts and engaging in hand-to-hand combat. On October 2, 1552, Kazan fell to Ivan's forces.

The Muscovite breakout from the Muslim cordon around its eastern and southern periphery continued with the defeat in 1556 of the Astrakhan Khanate, another successor of the Golden Horde. Strategically located on the Caspian Sea, some 800 miles from Moscow, Astrakhan gave Muscovy a port on the doorstep of the rival Safavid (centered in modern-day Iran), Ottoman (centered in Turkey), and Shaybanid (centered in Central Asia) empires.