Post-translational modifications (PTMs) regulate protein structure and function. Lysine methylation abundantly decorates histone proteins and has recently been detected on non-histone proteins. In particular, the tumor suppressor and transcription factor p53 has provided a model for lysine methylation on a non-histone protein. As found for histones, lysine methylation is dynamic and can be reversed by demethylation. Lysine methylation regulates function via several distinct mechanisms. Methyl lysine provides docking sites for binding of effector proteins. Methylation can serve to inhibit alternate PTMs on the same lysine residue. In addition, lysine can be monomethylated, dimethylated, or trimethylated, and these levels of methylation correlate with distinct genomic locations and functions. Taking into account combinatorial activity with numerous other PTMs, lysine methylation provides enormous functional diversity and regulatory complexity.