The Notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms. Osteoimmunology comprises the interplay between the immune system and bone metabolism. Osteoclasts, cells that resorb bone, play a crucial role in bone metabolism. In this review, we discuss the role of Notch signaling in osteoimmunology that is crucial for physiological bone remodeling (such as in orthodontic tooth movement, where bone remodeling is in balance) and undue non-physiological Notch signaling which results in pathological bone remodeling (such as in rheumatoid arthritis and periodontitis, where bone remodeling is out of balance) from the point view of osteoclast differentiation. A proposal is made that Notch signaling not only controls immune system reaction but also interferes with osteoclast differentiation involved in the bone remodeling process. Therefore, Notch signaling could be a promising therapeutic target at conditions that cross link the immune system with the skeletal system.