Osteoclasts are specialized, multinucleated macrophages that resorb bone. Genetic experiments in mice revealed that the three families of transcription factors, nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), and nuclear factor of activated T-cells (NFAT) are each essential for osteoclast differentiation. Macrophage colony stimulating factor (M-CSF), receptor activator of NF-kappaB ligand(RANKL), and other osteoclastogenic ligands activate the NF-kappaB components p50 or p52, the AP-1 component c-Fos, and NFATc1 in osteoclast precursors. Consequently, diverse groups of genes are transcribed, including those encoding tartrate-resistant acid phosphatase (TRAP), calcitonin receptor, cathepsin K and interferon-beta. Surprisingly, recent studies have begun to uncover a linear relationship among these transcription factors, including the c-Fos-NFATc1 transcriptional activation cascade.