Carbonic anhydrases (CAs; EC 4.2.1.1) are well known zinc metalloproteins involved in the catalysis of a very simple but essential physiological reaction: carbon dioxide hydration to bicarbonate and proton. These enzymes are of clinical relevance in cancer therapy as among the 15 isoforms known in humans, two cell surface CA isoforms, namely CA IX (almost exclusively associated with tumors) and CA XII (overexpressed in some tumor types) are involved in tumorigenesis. Targeting the tumor associated isoforms IX is now considered as a pertinent approach for the development of new cancer therapeutics against hypoxic tumors. Different approaches and new family of pharmacological agents were described in the last 5 years for obtaining compounds that specifically target CA IX over the ubiquitous cytosolic off-target isoforms CA I and CA II. The aim of this review is to give a comprehensive update on the reported discoveries in the field of CA IX inhibitors with an emphasis on the new families of compounds which reach in vivo/preclinical studies for their potential in cancer therapy.