The nuclear factor of activated T-cells (NFAT) family of transcription factors specify developmental pathways and cell fate in vertebrates. NFATc1, in particular, is crucial to multiple seemingly unrelated biologic processes, including heart valve formation, T-cell activation, osteoclast development, and the mitigation of hair follicle stem cell proliferation. Here, we review how our recently generated NFATc1 conditional knockout mouse has contributed to our understanding of this transcription factor in inflammatory and musculoskeletal conditions and their treatment.