While different markers for cancer diagnosis have been known for at least a decade, the systematic search for biomarkers emerged only several years ago. In this article, I will concentrate on DNA methylation as a dynamic and robust platform for the development of cancer-specific biomarkers. Simultaneous analysis of a growing number of independent methylation events can create increasingly more precise and individualized diagnostics. The differential detection of methylated and unmethylated DNA can be accomplished through either chemical modification or digestion with methylation-sensitive restriction enzyme(s). The benefits and potential pitfalls of both these approaches for clinical sample analysis will be addressed.