Although bisphosphonates were first used as therapeutic agents to inhibit bone resorption in the early 1970s, their mode of action at the molecular level has only become fully clear within the last few years. One of the reasons for this lack of understanding was the difficulty in isolating large numbers of pure osteoclasts for biochemical studies. In the last decade, the identification of appropriate surrogate models that reflected the antiresorptive potencies of bisphosphonates, such as Dictyostelium slime molds and macrophages, helped overcome this problem and proved to be instrumental in elucidating the molecular pathways by which these compounds inhibit osteoclast-mediated bone resorption. This brief review summarizes our current understanding of these pathways.