Members of the CD44 family of transmembrane glycoproteins, in particular CD44v6 isoforms, were shown to be metastatic determinants of rat pancreatic tumour cells back in the early 1990s. Furthermore, the expression of several CD44 proteins correlates with aggressive stages of various human cancers. Because of the frequent and homogeneous expression of CD44v6 isoforms in squamous cell carcinoma, antibodies recognising these proteins were used in clinical trials for patients suffering from head and neck squamous cell carcinoma (HNSCC). Although the phase I clinical trials looked promising, the studies were abruptly ended after the death of a patient. Despite the termination of the trials, CD44 certainly remains a valid target for anti-cancer therapy. In this review, alternative strategies targeting CD44 functions are presented. These functions include the binding to hyaluronan (HA), the collaboration with osteopontin and the contribution of CD44 isoforms to receptor tyrosine kinase (RTKs) activation. These new attempts led to the development of peptides that interfere for example with HA binding and that might be used to induce apoptosis in mammary carcinoma or to prevent homing of leukaemia stem cells. Other peptides block RTK activation and thereby inhibit tumour angiogenesis and metastatic spread.