Leiomyosarcomas (LMS) are mesenchymal malignancies with smooth muscle differentiation that most commonly arise in the uterus, retroperitoneum, and extremity. Clinical course is variable, and management differs by site of origin. Recently completed and ongoing clinical trials are optimizing LMS management, and multidisciplinary care by an expert team is essential to navigate the nuances and provide optimal care. Advances in molecular characterization have improved diagnosis and identification of novel prognostic factors and systemic therapies. This article provides an overview of LMS presentation, diagnosis, molecular features, and clinical management, and highlights advancements in LMS biology and treatment.