Although it is clear that genetic alterations are critical for the initiation and maintenance of human cancer, it is also becoming evident that epigenetic changes may be essential for the development of these diseases as well. The best studied of these latter processes is heritable transcriptional repression of genes associated with aberrant DNA hypermethylation of their promoters. Herein we review how very early occurrence of these gene silencing events may contribute to loss of key gene functions which result in disruption of cell regulatory pathways that may contribute to abnormal cell population expansion. These altered regulatory events may then provide a setting where mutations in the same disrupted pathways may be readily selected and serve to lock tumor progression into place. This hypothesis has potential impact on means to prevent and control cancer and for the use of epigenetic markers for cancer risk assessment and early diagnosis.