Cytosine methylation is a heritable modification of DNA in mammalian cells, and has a determinant impact on long-term gene repression and genome stability. Genomic methylation patterns, which remain generally stable in the adult, become profoundly altered in most human tumors. While discrete DNA segments become hypermethylated in cancer cells, many more sequences become hypomethylated. This review discusses our current understanding of the mechanisms that lead to DNA hypomethylation in tumors. Evidence suggests that methylation losses are not random, but rather evolve into mosaic hypomethylation patterns. It is proposed that such hypomethylation patterns result from a historical event of transient DNA demethylation, and that transcriptional regulators contribute to determining which regions escape remethylation and remain therefore unmethylated. Finally, possible stages of tumor development during which the transient DNA demethylation process may take place will be discussed.