During the past two decades an overwhelming amount of knowledge has been acquired on the molecular genetics of human cancer. It is now evident that cancer is essentially a genetic disease, arising from inherited and/or somatically acquired mutations at different genetic loci, and that tumourigenesis is a multistep process. Gene mapping studies of inherited cancer syndromes have resulted in the identification of many genes implicated in the initiation of tumours. Importantly, alterations of the same genes were also found to play a role in the development of common, non-familial tumours. The genes involved belong to distinct functional classes, and include proto-oncogenes and tumour suppressor genes, which are regulators of cellular growth and proliferation, cell adhesion and programmed cell death. Another class of cancer susceptibility genes consists of DNA repair genes, which are involved in maintaining genomic stability. In unravelling the genetic basis of cancer, the localization and identification of genes involved in tumourigenesis can be considered as the 'easy' part; determination of the normal physiological function of these genes and their precise role in tumourigenesis has proved to be much more difficult. In this review, we highlight some of the major breakthroughs in the field of cancer genetics, and discuss recent insights in the putative role of proto-oncogenes, tumour suppressor genes and DNA repair genes in the initiation and progression of cancer. Also, we point to some of the challenges to be faced in the coming years.