Anchorage independence and motility are hallmarks of tumor cell growth. Tumor cell growth and morphology can be normalized by contact with nontransformed cells. The Src tyrosine kinase phosphorylates specific sites on the focal adhesion adaptor protein Crk-associated substrate (Cas) to promote nonanchored cell growth and migration. We studied the effects of Src and Cas on the expression of >14,000 genes to identify molecular events that underlie these activities. Gene expression in tumor cells that were normalized by neighboring nontransformed cells was used as an additional filter to identify genes that control metastatic cell growth. This process enabled the identification of genes that play roles in anchorage-independent cell growth and migration. One candidate, four and a half LIM domains 1 (Fhl1), acts as a transcriptional regulator that can associate with cell junctions as well as with the nucleus. We show here that Src phosphorylates Cas to block Fhl1 expression. In addition, suppression of Fhl1 is required for Src to promote tumor cell growth. These data show that Fhl1 is a tumor suppressor gene that acts downstream of Src and Cas to specifically block anchorage-independent cell growth and migration. Moreover, Fhl1 was suppressed in tumors from several human tissues. Thus, identification of how Fhl1 controls fundamental aspects of tumor cell growth and metastasis may lead to the development of novel markers that can be used to diagnose human clinical specimens as well as open innovative avenues of investigations aimed at developing reagents that target cancer cells while minimizing damage to normal cells.