Histone deacetylases (HDACs) are a class of enzymes that remove acetyl from the ε-N-acetyl lysine of histones, allowing histones to wrap DNA more tightly. HDACs play an essential role in many biological processes such as gene regulation, transcription, cell proliferation, angiogenesis, migration, differentiation and metastasis. As a result, HDACs represent an excellent target for anti-cancer drug discovery. The search for histone deacetylase inhibitors (HDACis) has been intensified in the last decade with numerous HDACis being discovered, and some of them have reached the market. However, currently available HDACis are mostly non-isoform selective and suffer from several drawbacks such as limited efficacy, drug resistance, and toxicities. Therefore, isoform-selective HDACis and HDACis with dual targeting capabilities have attracted much attention from academia to industry in the past 5 years, and great advances have been achieved in this area. In this paper, we summarize recent progress on HDACis with dual targeting capabilities and their potential application to cancer treatment.