Changes in genomic methylation and its significance in carcinogenesis is in the spotlight once again, though the focus is not on the usual suspects, DNA hypermethylation and tumour suppressor gene (TSG) silencing. Several recent reports provide compelling evidence of the relevance of genomic hypomethylation in cancer. These findings provide the best evidence so far that links the loss of DNA methylation and chromosomal instability with cancer development. This review article discusses these recent findings and reflects on the antithetical association between DNA methylation and carcinogenesis and the re-examination of studies performed almost two decades ago.