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The covalent post-translational modification of proteins by ubiquitination not only influences protein stability and half-life, but also several aspects of protein function including enzymatic activity, sub-cellular localization, and interactions with binding partners. Protein ubiquitination status is determined by the action of large families of ubiquitin ligases and deubiquitinases, whose combined activities regulate many physiological and cellular pathways. The Ubiquitin Specific Protease (USP) family is one of 8 subfamilies of deubiquitinating enzymes composed of more than 50 members. Recent studies have shown that USP15 plays a critical role in regulating many aspects of immune and inflammatory function of leukocytes in response to a broad range of infectious and autoimmune insults and following tissue damage. USP15 regulated pathways reviewed herein include TLR signaling, RIG-I signaling, NF-kB, and IRF3/IRF7-dependent transcription for production of pro-inflammatory cytokines and type I interferons. In addition, USP15 has been found to regulate pathways implicated in tumor onset and progression such as p53, and TGF-β signaling, but also influences the leukocytes-determined immune and inflammatory microenvironment of tumors to affect progression and outcome. Hereby reviewed are recent studies of USP15 in model cell lines in vitro, and in mutant mice in vivo with reference to available human clinical datasets.