Skeletal distortions impose grave health disparities with potentially devastating consequences, including bone pain, immobility, and morbidity. Bone erosion is chiefly caused by hyperactive osteoclasts summoned to bone in response to circulating factors produced by tumor and inflammatory cells. Intense research in the past two decades has identified crucial elements and intricate circulatory systems that maintain and exacerbate inflammatory osteolysis. This progress led to better understanding of the mechanisms underlying this response and to developing advanced therapeutic interventions. Nevertheless, the multifactorial causes of inflammatory osteolysis continue to impose a great challenge for these therapies. This article provides an overview of some of the prominent facets contributing to this process.