As an important player in stem cells and cancer, CD44 is expressed in multiple isoforms via alternative mRNA splicing. Whether, and if so, how various isoforms play distinct roles in normal stem cells and tumorigenesis remains unclear. In this issue of Oncogene, Zeilstra et al. report studies showing that intestinal stem cells express a specific CD44 variant that promotes intestinal tumorigenesis induced by the activation of Wnt signaling, whereas the more commonly expressed standard CD44 isoform is not expressed by stem cells and does not promote tumor formation. This finding demonstrates an isoform-specific function of CD44 in intestinal stem cells and tumorigenesis.