Epithelial-mesenchymal transition (EMT) has been widely accepted as the early stage of tumor metastasis, which is accomplished by a group of transcription factors based on cancer genome. However, with the progress of epigenome profiling technique, it has been demonstrated that aberrant histone modifications especially acetylation play an important role in EMT and cancer metastasis. Besides this, numerous studies have elucidated the mechanisms of histone acetyltransferases and deacetylases involved in EMT. Moreover, the network of these histone-related proteins and those transcription factors that play key roles in EMT is under increasing investigation. In addition, the crosstalk among deoxyribonucleic acid methylation, histone acetylation and micro Ribonucleic acid, three major epigenetic modifications, is also an important part in tumor progression. Here, we explore the mechanisms of histone acetylation in EMT and discuss the potential clinical strategies using the epigenetic drugs.