It was only 25 years ago that the concept of cancer as a genetic disease began to gain widespread acceptance. It is encouraging to note that recurrent molecular pathways critical to the genesis and evolution of human sarcomas are being elucidated through molecular and cytogenetic techniques. It is also important to remember that molecular genetics and cytogenetics are still in their infancy. In this review, we have barely touched on the tremendous amount of information that has developed in sarcoma genetics and cytogenetics. As this synergistic evolution of genetic changes in human sarcomas becomes better understood, new and better therapeutic strategies aimed at circumventing these processes will be developed. But the biologic and genetic redundancies intrinsic to mammalian cells continue to allow tumors to adapt and resist chemotherapeutic agents. Understanding sarcoma progression at the molecular level will allow, therefore, for the identification of better diagnostic markers, the development of new therapeutic strategies, and the ability to select the most effective and least toxic combination of antitumor therapies for a patient.