The successful treatment of many human diseases, including cancer, has come to be considered a major challenge, as patient response to therapy is difficult to predict. Recently, considerable efforts are being focused on the development of new tools to meet the growing demand for personalized medicine. With few exceptions, synthetic compounds have been unable to meet initial expectations for their clinical use. The last twenty years have been characterized by the failure of several drugs in advanced clinical development, possibly due to the insufficient understanding of molecular pathways underlying their mechanism of action. Although the biodiversity of compounds found in nature has been poorly explored until now, the field of naturally occurring drugs is rapidly expanding. Here, we review the current knowledge on the use of natural compounds with particular emphasis on those that display a chromatin remodeling effect coupled with anticancer action.