In 1449, Kantō Kanrei Ashikaga Shigeuji killed his Uesugi deputy in order to check the family's power.

The Uesugi's deposition of Shigeuji left them as the predominant power in the Kantō region, and the clan was able to grow rapidly.

While the Ōgigayatsu were less numerous than the Yamanouchi, they held on to power due to Ōta Dōkan's construction of the Edo Castle in the 1450s.

The first head of this rising clan, Hōjō Sōun, allied himself with Nagao Tamekage, Deputy Constable of Kamakura, and would go on to become one of their strongest rivals.

However, the Ōgigayatsu branch would ultimately come to an end with the death of Uesugi Tomosada during a failed siege of Kawagoe castle later that year.

After Yonezawa entered debt and experienced famine in the 1750s, the current daimyō Uesugi Shigesada considered giving the territory back to the shogunate.

When the Uesugi clan faced the threat of abolition due to the sudden death of Tsunakatsu (1639–64), they were saved by Hoshina Masayuki.

Alongside the Sendai Domain (Date clan), they led the Northern Alliance (Ōuetsu Reppan Dōmei) and fought against the new government forces, but after repeated defeats, they eventually surrendered.

[3] The Meiji Restoration in 1868 brought the abolition of the han system, that is, the end of the domains, the feudal lords, and the samurai class.

Its present head, Uesugi Kuninori (born 1942), is a professor at the Institute of Space and Astronautical Science, Ministry of Education.