Recent studies have elucidated unanticipated connections between the immune and skeletal systems, and this relationship has led to the development of a new field known as osteoimmunology. The goal of research in this field is to: (1) further understand how the bone microenvironment influences immune cell ontogeny and subsequent effector functions, and (2) translate basic science findings in bone biology to clinical applications for autoimmune diseases that target the skeleton such as rheumatoid arthritis (RA). In this review, we will examine the recent findings of the interplay between the immune and skeletal systems. This discussion will focus on the cells and signaling pathways in osteoimmune interactions and how innate and adaptive immune effector cells as well as cytokines and chemokines play a role in the maintenance and dysregulation of skeletal-immune homeostasis. We will also discuss how immunomodulatory biologic drugs, which specifically target these cells and effector molecules, have transformed the treatment of autoimmune mediated inflammatory diseases (IMIDs) and metabolic bone diseases such as osteoporosis.