Because epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and the promotion of tumorigenesis in cancers, novel compounds endowed with histone deacetylase (HDAC) inhibitory activity are an attractive therapeutic approach. Indeed, the potential of HDAC inhibitors for cancer therapy has been explored in preclinical models, and some agents approved for hematologic malignancies have reached the clinical setting. HDAC inhibitors are able to mediate the induction of both apoptosis and autophagy, which are related to anticancer activity in a variety of cancer cell lines. Given the inherent resistance to apoptosis that characterizes cancer, the targeting of alternative pathways is an attractive strategy to improve anti-tumor therapy. The activation of autophagy represents novel cancer treatment targets. This paper aims to critically discuss how the anticancer potential of HDAC inhibitors may elicit a response to human cancers through different cell pathways leading to cell death.