CD44 is a family of single-span transmembrane glycoproteins. Members of this family differ in the extracellular domain where ten variant exons are either excluded or included in various combinations. CD44 isoforms participate in many physiological processes including hematopoiesis, regeneration, lymphocyte homing and inflammation. Most importantly, they are involved in pathological processes and in particular in cancer. In several types of tumors, CD44 together with other antigens specifies for cancer stem cell populations. Mechanistically, CD44 proteins act as receptors for hyaluronan, co-receptor for receptor tyrosine kinases (RTKs) or G-protein-coupled receptors or provide a platform for metalloproteinases. For all these reasons, targeting CD44 may be a successful approach in cancer therapy. In this review, we discuss the various possibilities of targeting CD44. Among these are the production of CD44 ectodomains, antibodies, peptides or aptamers. Also inhibition of CD44 expression has been proposed. Finally, the function of CD44 as a hyaluronan receptor was also taken advantage of. We are convinced that the success of these therapies will depend on an increased understanding of the molecular functions of specific CD44 isoforms in particular in cancer stem cells.