The genetic changes leading to the development of human cancer are accompanied by alterations in the structure and modification status of chromatin, which represent powerful regulatory mechanisms for gene expression and genome stability. These epigenetic alterations have sparked interest into deciphering the regulatory pathways and function of post-translational modifications of histones during the initiation and progression of cancer. In this review we describe and summarize the current knowledge of several histone lysine methyltransferase and demethylase pathways relevant to cancer. Mechanistic insight into histone modifications will pave the way for the development and therapeutic application of “epidrugs” in cancer.