After Takamoto died, Motonari not only acted as the guardian of his grandson, Terumoto MORI (the 54th), but also possessed the Chugoku region (the provinces of Aki, Suo, Nagato, Bicchu, Bingo, Inaba, Hoki, Izumo, Oki, and Iwami), after destroying the clan's enemy, the Amago clan.
隆元の没後はその子の毛利輝元（54代）を後見しつつ、1566年、仇敵の尼子氏を滅ぼして、中国地方（安芸・周防国・長門国・備中国・備後国・因幡国・伯耆国・出雲国・隠岐国・石見国）を領有した。