Pathological bone loss diseases (osteolysis, Paget’s diseases) are commonly caused by the excessive differentiation and activity of osteoclasts. The Rho GTPases family members Rac1/2 (Rac1 and Rac2) have been reported for their special role in exerting multiple cellular functions during osteoclastic differentiation, which includes the most prominent function on dynamic actin cytoskeleton rearranging. Besides that, the increasing studies demonstrated that the regulating effects of Rac1/2 on the osteoclastic cytoskeletal organization are through the GEFs member Dock5. Although the amount of relevant studies on this topic is still limited, several excellent studies have been reported that extensively explored the molecular mechanisms involved in Rac1/2 and Dock5 during the osteoclastogenesis regulation, as well as their role as the therapeutic target in bone loss diseases. Herein, in this review, we aim to focus on recent advances studies for extensively understanding the role of Rho GTPases Rac1/2 and Dock5 in osteoclastogenesis, as well as their role as a potential therapeutic target in regulating osteoclastogenesis.