Bone homeostasis is maintained throughout life by coordinated osteocyte regulation of bone resorption by osteoclasts and bone formation by osteoblasts. Many pathologic bone states such as osteoporosis, inflammatory arthritis, and bone metastasis have increased numbers, survival, or function of osteoclasts resulting in enhanced bone resorption outpacing bone formation. Differentiation, survival, recruitment, and resorptive activity of osteoclasts and their precursors are highly regulated by intracellular signals stimulated by soluble mediators, extracellular matrix, and adjacent cells. In this issue of Arthritis & Rheumatology, Gyoőri and colleagues describe a specific role for the enzyme phosphoinositide 3-kinase β (PI3Kβ) in the regulation of osteoclast-mediated bone resorption (1), suggesting that a specific inhibitor of this enzyme isoform may be a novel antiresorptive agent.