Intense recent efforts have gradually advanced our understanding of the heterogeneous processes underpinning the development and evolution of myriad sarcoma subtypes. These mechanistic insights are gradually being translated into novel treatment approaches that are beginning to “move-the-needle” in sarcoma therapeutics. These advances run the entire gamut of cytotoxic therapies, kinase inhibitors, epigenetic therapies, immunotherapy and cellular therapy, buttressed by significant improvements in biomarker science to target unique vulnerabilities that can be unique to, or span across, specific histologic subtypes. It is hoped that the aggregate of these individually small improvements will move the field forwards in a meaningful way and mitigate, to some degree, the challenges inherent in generating large-scale systematic evidence in individually uncommon cancers.