Sarcomas comprise a heterogeneous group of malignancies that are derived from mesenchymal cells, which under normal circumstances lead to the development of connective tissues such as bone, muscle, fat, and cartilage. During the past decade, insight has been gained regarding the aberrancies that occur during normal development that result in mesenchymal cells transforming into sarcomas. More recently, these insights have led to the development of successful therapies that target the specific mechanisms inherent to individual sarcomas. This overview discusses some of the aberrant molecular mechanisms shared in sarcomas and reviews several sarcoma subtypes in which the most advances have been made. Finally, the ways in which these advances in basic science are translating into and redefining clinical practice are highlighted.