Although the cloning of tumor suppressor genes has proved to be an arduous task, often involving several years of labor intensive cloning strategies, a greater understanding of neoplastic progression will be made once the function and role of these genes have been sorted out. To fully appreciate the state at which this field of research currently is, however, one must understand that the road to tumor suppression was paved by both somatic cell hybridization and chromosome transfer studies. Although regarded by many as laboratory artifact, somatic cell hybridization has provided strong circumstantial evidence, if not formal proof, for the existence of tumor suppressor genes. In further reducing the complexity associated with whole genome transfer, single chromosome transfer was subsequently developed as a refinement to this technique so that one could unequivocally correlate suppression with a particular chromosome. We have learned from these studies that single chromosomes harbor the genetic information necessary to reverse the malignant phenotype associated with cancer cells. Furthermore, multiple tumor suppressor loci are now known to exist, with one to several different loci associated with a given tumor type. In this review, we present evidence for tumor suppressor genes and discuss the early studies that led to their discovery.