The osteoclast is hematopoietic in origin and is the primary bone-resorbing cell derived from monocyte/macrophage lineage. Tumor necrosis factor (TNF) family member, RANK ligand (RANKL) expressed on marrow stromal/osteoblast cells in response to several osteotropic factors, is critical for osteoclast precursor differentiation to form multinucleated osteoclasts, which resorb bone. M-CSF is required for proliferation, survival, and expression of receptor activator of nuclear factor kappa B (RANK) in osteoclast precursors. The interaction of RANKL-RANK results in activation of various signaling cascades during osteoclast development and activation. The osteoclast is an autocrine/paracrine, intracrine regulatory cell that produces factors such as IL-6, Annexin II, TGF-β, OIP-1/hSca, which influence its own formation and activity. In addition, integrin expression in osteoclasts mediate cell-matrix and cell-cell interactions in the bone microenvironment through specific signaling pathways resulting in cytoskeletal organization, polarization, and activation of osteoclasts to resorb bone. Recent molecular genetic studies have identified several transcription factors, such as NF-κB, c-Fos, MITF, and NFATc1, which are essential for osteoclast differentiation. Although a wide variety of molecules, including the reactive oxygen species (ROS) that are differentially regulated during osteoclastogenesis, the precise signal transduction pathways, and molecular mechanisms underlying the gene expression in osteoclasts, are just beginning to be defined. In this review, we discuss the molecular regulatory mechanisms operative during osteoclast differentiation, bone resorption, and survival.