Much of the progress in systemic therapy for sarcomas was accomplished in the first half of the last 5 decades. Various chemotherapeutic agents were tested in the 70s through the 80s and became part of the standard of care for this patient population. During the decade of the 90s, dose intensification became feasible as a result of improved supportive care and the availability of growth factors, thus maximizing the therapeutic potential of this class of agents. However, response rates and survival plateaued and it became obvious that newer and mechanistically different agents were needed to improve the therapeutic index and gain further enhancement of outcomes. Since early 2000, primarily inspired by the experience with imatinib in gastrointestinal stromal tumors (GISTs), several targeted therapies have been tested in sarcomas with modest success. The major limitations encountered include the lack of drivers and actionable targets for bone and soft tissue sarcomas with complex genomic profiles. Continued investigations and sequencing of larger numbers of these rare and heterogeneous malignancies could shed some light on a path toward improved outcomes.