Epigenetic events like DNA methylation are known to regulate gene expression, and dysregulation of these events is associated with neoplastic proliferation. Here, we provide a step-by-step review of the approach that has gradually developed to identify critical DNA methylation during neoplasia. DNA methylation has first been tightly linked to the regulation of gene expression and functions. Next, the clinical importance of such DNA methylation has been probed by inducing loss of the maintenance of normal DNA methylation, which has been found to trigger onset of disease. Methylation changes can be signal-specific and lineage-specific, providing a record what cells have encountered and what they have become. Comparison of methylation associated with normal cellular differentiation and abnormal cell fate changes is expected to uncover critical methylation changes. We also propose a specific scheme that can be used to excavate critical DNA methylation associated with cell evolution.