The term giant cell-rich tumors of bone refers to a shared morphologic pattern in a group of different osseous lesions, that is, the abundance of osteoclastlike giant cells. Fitting with a broad spectrum of clinical presentations and biological behavior, the recent detection of characteristic molecular alterations in giant cell tumor of bone (H3-3), nonossifying fibroma (KRAS, FGFR1), giant cell granuloma of the jaws (KRAS, FGFR1, TRPV4), and aneurysmal bone cyst (USP6) have contributed significantly to the biological understanding of these morphologically related but clinically distinct lesions and their systematic classification, highlighting differences and pathogenic relationships.