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The was descended from the Seiwa Genji, a branch of the Minamoto clan, and ultimately from Emperor Seiwa himself, through the Ashikaga clan. It produced many prominent officials in the Ashikaga shogunate's administration. In the Edo period, the Hosokawa clan was one of the largest landholding daimyo families in Japan. In the present day, the current clan head Morihiro Hosokawa, has served as Prime Minister of Japan.
Ashikaga Yoshisue, son of Ashikaga Yoshizane, was the first to take the name of Hosokawa. Hosokawa Yoriharu, a Hosokawa of the late Kamakura period, fought for the Ashikaga clan against the Kamakura shogunate. Another, Hosokawa Akiuji, helped establish the Ashikaga shogunate.
The clan was also one of three families to dominate the post of Kanrei (Shogun's deputy), under the Ashikaga shogunate. One such individual was Hosokawa Yoriyuki. At the beginning of the Ashikaga's rule, the Hosokawa were given control of the entirety of Shikoku. Over the course of this period, members of the Hosokawa clan were Constables (shugo) of Awa, Awaji, Bitchu, Izumi, Sanuki, Settsu, Tamba, Tosa, and Yamashiro Provinces.
A conflict between Hosokawa Katsumoto, the fifth Kanrei, and his father-in-law Yamana Sōzen, over the shogunate's succession, sparked the Ōnin War, which led to the fall of the shogunate and a period of 150 years of chaos and war, known as Sengoku. Following the fall of the Ashikaga shogunate, which was based in Kyoto, control of the city, and thus obstensibly the country, fell into the hands of the Hosokawa clan (who held the post of Kyoto Kanrei - Shogun's deputy in Kyoto) for a few generations.
Katsumoto's son, Hosokawa Masamoto, held power in this way at the end of the 15th century, but was assassinated in 1507. After his death, the clan became divided and was weakened by internecine fighting. What power they still had, however, was centered in and around Kyoto. This gave them the leverage to consolidate their power to some extent, and came to be strong rivals with the Ōuchi family, both politically, and in terms of dominating trade with China. The Hosokawa remained in Kyoto for roughly one hundred years, fleeing the city when it was attacked by Oda Nobunaga.
The Hosokawa of Kokura (later Kumamoto) became the "main" line of the Hosokawa clan during the Edo period. Hosokawa Gracia, the wife of Hosokawa Tadaoki, was one of the most famous samurai converts to Christianity; she was also the daughter of Akechi Mitsuhide.
The Hosokawa sided with Tokugawa Ieyasu against Ishida Mitsunari during the decisive Sekigahara Campaign, and thus were made fudai (inside) daimyo under the Tokugawa shogunate. They were given Higo province, with an income of 540,000 koku, as their han (fief).
Though the Hosokawa domain was far from the capital, on Kyūshū, they were among the wealthiest of the daimyo. By 1750, Higo was one of the top producers of rice, and was in fact counted as a standard by the Osaka rice brokers. The domain suffered from serious economic decline after that, as most domains did, but the sixth lord, Hosokawa Shigekata (1718–1785, r. 1747-1785) instituted a number of reforms which turned the situation around. He also founded a Han school, Jishuukan, in 1755. In later years, it produced many scholars such as Yokoi Shonan.
In 1787, the main family line descended from Tadatoshi became extinct with the death of the 7th lord, Shigekata's son Harutoshi (1758–1787; r. 1785-1787). He was succeeded by his distant cousin Narishige, the sixth Lord of Udo (1755-c1835, r. 1787-1810) a direct descendant of Tadatoshi's younger brother Yukitaka (1615–1645). In 1810, Narishige abdicated his title in favor of his elder son Naritatsu (1788–1826, r. 1810-1826), who succeeded as the ninth lord of Kumamoto. Naritatsu died without an heir in 1826, and was succeeded by his nephew Narimori (1804–1860, r. 1826-1860), the son of Naritatsu's younger brother Tatsuyuki (1784–1818), who was the seventh lord of Udo.
Following the death of Narimori in 1860, his elder son Yoshikuni (1835–1876, r. 1860-1871) succeeded him as the eleventh and final ruling lord of Kumamoto.
There were four major branches of the Hosokawa clan in the Edo period, each of which held the title of daimyo. Another two branches of the family, under the Nagaoka surname, served the Hosokawa of Kumamoto as karō. The residence of one of those families, Hosokawa Gyōbu mansion (細川刑部邸 Hosokawa Gyōbu-tei?), is still extant, and is a Tangible Cultural Property of Kumamoto Prefecture.
During the Boshin War of 1868-69, the Hosokawa of Kumamoto, Kumamoto-Shinden, and Udo sided with the imperial government. Its forces took part in the Battle of Aizu and the Battle of Hakodate, among others.
Following the abolition of the feudal class in 1871, the Hosokawa clan and its branches were made part of the new nobility in the Meiji era. The head of the main family line (Kumamoto) was given the hereditary title of marquis (kōshaku), while the heads of the secondary branches became viscounts (shishaku); the titles became obsolete in 1947. The present head of the main family line, Morihiro Hosokawa, former Prime Minister of Japan, is a descendant of the Hosokawa of Kumamoto.