Sarcomas are a heterogeneous group of malignancies that arise from cells of a mesenchymal origin. Surgery forms the mainstay of the treatment of most patients with localized sarcoma and might be followed or preceded by chemotherapy and/or radiotherapy. In the metastatic setting, systemic treatments tend to improve survival and control symptoms. However, the adverse events and sometimes disappointing outcomes associated with these empirical approaches to treatment indicate a need for new approaches. The advent of next-generation sequencing (NGS) has enabled more targeted treatment of many malignancies based on the presence of specific alterations. NGS analyses of sarcomas have revealed the presence of many alterations that can be targeted using therapies that are already used in patients with other forms of cancer. In this Review, we describe the genomic alterations considered to define specific nosological subgroups of sarcoma and whose contribution to oncogenesis provides a biological rationale for the use of a specific targeted therapy. We also report several less successful examples that should guide researchers and clinicians to better define the extent to which the identification of driver molecular alterations should influence the development of novel treatments.