Histone acetyltransferases (HATs) catalyzing N-epsilon-lysine or N-alpha-terminal acetylation on histone and non-histone substrates are important epigenetic regulators controlling gene expression and chromatin structure. Deregulation of these enzymes by genetic or epigenetic alterations accompanied by defects in gene transcription have been implicated in oncogenesis. Therefore, these enzymes are considered promising therapeutic targets, offering new horizons for epigenetic cancer therapy. However, recent observations suggest that these enzymes function as both oncogenes and tumor suppressors. In this review, we present the current evidence demonstrating that individual HATs can either prevent cancer cell proliferation or drive malignant transformation depending on the molecular context and cancer type. We therefore advocate that future therapeutic interventions targeted toward these enzymes should carefully consider the fact that HATs commonly have a two-sided role in carcinogenesis.