The classical theory of recessive oncogenesis predicted a mutational mechanism for the inactivation of tumor suppressor (TS) genes. This prediction has been amply confirmed, but an alternative, nonmutational, pathway for loss of TS gene activity has also come into focus. For some TS genes, this epigenetic pathway is more frequent than the mutational one. The best-studied DNA modification that correlates with epigenetic gene silencing is methylation of cytosine residues in CpG sequences, and CpG methylation has recently been linked to an even more general mechanism of epigenetic silencing, histone deacetylation. From a combination of descriptive studies and manipulative experiments, some hints of mechanisms for epigenetic silencing of TS genes in cancer cells are beginning to emerge. Here, I discuss several well-documented examples of epigenetic gene silencing in human cancers. I then consider potential mechanisms for de novo methylation of TS genes in cancer. These include spreading of DNA methylation from repetitive sequences into promoter-associated CpG islands secondary to loss of transcriptional activator proteins, gain of methylation secondary to hyperexpression of transcriptional repressors, primary hypermethylation due to hyperexpression of methyltransferases, and interallelic transfer of methylation via gene pairing. In some cancers, environmental pressures that select for a hypermethylating cellular phenotype may drive these processes.