As Middle-Eastern merchants traded with the and other people living on the western slopes of the Ural as far north as, since at least the 10th century medieval had been aware of the existence of the mountain range in its entirety, stretching as far as to the Arctic Ocean in the north. The first Russian mention of the mountains to the east of the East European Plain is provided by the, when it describes the expedition to the upper reaches of the in 1096. During the next few centuries Novgorodians engaged in with the local population and collected tribute from and Great Perm, slowly expanding southwards. The rivers and were first mentioned in the chronicles of 1396 and 1468, respectively.

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In 1430 the town of (Kama Salt) was founded on the at the foothills of the Ural, where salt was. Captured Perm, Pechora and Yugra from the declining Novgorod Republic in 1472. With the excursions of 1483 and 1499–1500 across the Ural Moscow managed to subjugate Yugra completely. A fragment of 's map Nevertheless, around that time early 16th century Polish geographer in his influential Tractatus de duabus Sarmatiis (1517) argued that there were no mountains in Eastern Europe at all, challenging the point of view of some authors of Classical antiquity, popular during the. Only after Sigismund von Herberstein in his (1549) had reported, following Russian sources, that there are mountains behind the Pechora and identified them with the Ripheans and Hyperboreans of ancient authors, did the existence of the Ural, or at least of its northern part, become firmly established in the.

The Middle and Southern Ural were still largely unavailable and unknown to the Russian or Western European geographers. In 1910 In the 1550s, after the had defeated the and proceeded to gradually annex the lands of the Bashkirs, the Russians finally reached the southern part of the mountain chain. In 1574 they founded. The upper reaches of the Kama and Chusovaya in the Middle Ural, still unexplored, as well as parts of Transuralia still held by the hostile, were granted to the by several decrees of the tsar in 1558–1574. The Stroganovs' land provided the staging ground for 's.

Yermak crossed the Ural from the Chusovaya to the around 1581. In 1597 Babinov's road was built across the Ural from Solikamsk to the valley of the, where the town of (Upper Tura) was founded in 1598. Customs was established in Verkhoturye shortly thereafter and the road was made the only legal connection between European Russia and Siberia for a long time. In 1648 the town of was founded at the western foothills of the Middle Ural. During the 17th century the first deposits of and ores,, and other minerals were discovered in the Ural. Iron and copper emerged.

They multiplied particularly quickly during the reign of. In 1720–1722 he commissioned to oversee and develop the mining and smelting works in the Ural. Tatishchev proposed a new copper smelting factory in, which would eventually become the core of the city of and a new iron smelting factory on the, which would become the largest in the world at the time of construction and give birth to the city of. Both factories were actually founded by Tatishchev's successor,, in 1723.

Tatishchev returned to the Ural on the order of to succeed de Gennin in 1734–1737. Transportation of the output of the smelting works to the markets of European Russia necessitated the construction of the from Yekaterinburg across the Ural to Kungur and Yegoshikha (Perm) and further to Moscow, which was completed in 1763 and rendered Babinov's road obsolete. In 1745 gold was discovered in the Ural at and later at other deposits. It has been mined since 1747. The first ample geographic survey of the Ural Mountains was completed in the early 18th century by the Russian historian and geographer Vasily Tatishchev under the orders of Peter I. Earlier, in the 17th century, rich ore deposits were discovered in the mountains and their systematic extraction began in the early 18th century, eventually turning the region into the largest mineral base of Russia. One of the first scientific descriptions of the mountains was published in 1770–71.