Histone lysine methylation plays an important role in the regulation of gene expression and impacts many fundamental biological processes, such as cellular identity. Despite great efforts, the mechanisms behind the downstream consequences of histone methyl-recognition remain poorly understood. Here, we describe various methods to investigate specific histone lysine-methyl recognition, including the use of short peptides, histone octamers, and the more physiological nucleosomal arrays. We also discuss techniques that are well suited to assess functional aspects of binding as it relates to transcriptional regulation.