Expression cloning is a powerful approach to finding genes that induce appreciable changes in cultured cells. One way to use this technique in cancer research is to isolate cDNAs that induce flat reversion in transformed cells. Such screening, however, is inherently artificial, and therefore requires independent validation of the clinical relevance of isolated genes. Studies of the mechanisms of actions, physiological functions and mechanisms of regulation of these genes at various levels may enrich our knowledge of cancer biology and supplement our toolbox in developing new cancer diagnoses and therapies. In this article we discuss the promise, limitations and recent innovations in this approach, taking one transformation suppressor gene, RECK, as an example.