Tumor metastasis is one of the most life-threatening aspects of tumor progression in patients with cancer. One of the cell surface molecules that has been implicated to play an important role in tumor metastasis is CD44. Earlier results provide the initial optimism that CD44 isoform expression may be a marker for human cancers. However, more recent studies revealed that regulation of CD44 isoform expression is a complex and not well-understood phenomenon. Expression of CD44 in tumor cells can be regulated quantitatively by increasing the expression of one particular CD44 isoform or quantitatively by altering the expression of CD44 isoforms. Downregulation of CD44 is important in the metastasis of some tumor cells. We summarize some of the recent results on the potential of CD44 as a diagnostic or prognostic marker for patients with cancers.