In many solid tumors the rapidly proliferating cancer cells create an environment with insufficient oxygen supply. In response to this tumor hypoxia, cancer cells adapt gene expression to thrive in the altered microenvironment. One of these adaptations is the shift towards anaerobic glycolysis. Lactic acid accumulates hand-in-hand with carbon dioxide, leading to acidification of the extracellular environment. Carbonic anhydrase IX (CAIX) is one of the expressed genes required in response to hypoxia for cell survival, as its role in intracellular pH maintenance allows the cancer cells to adapt to the extracellular environment. In addition, CAIX stimulates the migratory pathways of cancer cells and the aggressive/invasive phenotype of tumors, and has been shown to play a key role in signaling cascades acting similar to a feed-forward regulator of its own expression. Hence CAIX expression in several tumor tissues indicates its relevance as a general marker of tumor hypoxia. Moreover, its expression is correlated to poor clinical outcome in several tumor types. In this review we describe the biochemical characteristics of CAIX and the regulatory pathways of its production. In addition we summarize the CAIX expression patterns in normal and cancerous tissues. Lastly, we discuss the physiological role of CAIX in the tumor microenvironment in terms of pH regulation, proliferation, cell motility, adhesion, invasiveness, and signaling, and how this identifies CAIX as an anti-cancer target.