The state of modification of histone tails plays an important role in defining the accessibility of DNA for the transcription machinery and other regulatory factors. It has been extensively demonstrated that the posttranslational modifications of the histone tails, as well as modifications within the nucleosome domain, regulate the level of chromatin condensation and are therefore important in regulating gene expression and other nuclear events. Together with DNA methylation, they constitute the most relevant level of epigenetic regulation of cell functions. Histone modifications are carried out by a multipart network of macromolecular complexes endowed with enzymatic, regulatory, and recognition domains. Not surprisingly, epigenetic alterations caused by aberrant activity of these enzymes are linked to the establishment and maintenance of the cancer phenotype and, importantly, are potentially reversible, since they do not involve genetic mutations in the underlying DNA sequence. Histone modification therapy of cancer is based on the generation of drugs able to interfere with the activity of enzymes involved in histone modifications: new drugs have recently been approved for use in cancer patients, clinically validating this strategy. Unfortunately, however, clinical responses are not always consistent and do not parallel closely the results observed in preclinical models. Here, we present a brief overview of the deregulation of chromatin-associated enzymatic activities in cancer cells and of the main results achieved by histone modification therapeutic approaches.