Normal adhering cells undergo apoptosis shortly after loss of adhesion to substratum, a phenomenon known as "anoikis." In-vitro-transformed cells and cancer-derived cells are able to survive and grow in the absence of anchorage to the extracellular matrix (ECM) and their neighboring cells. This represents one of the most important oncogenic properties of cancer cells. Integrin-ECM-mediated function is essential for survival and growth of normal adhering cells, while cancer cells are able to abrogate this requirement. This article will review and summarize the recent findings from our laboratory about the molecular signaling pathways important for the regulation of anchorage-independent survival and the growth of transformed fibroblasts and epithelial cells. Our study has shown that integrin-ECM-mediated signaling and cytoskeletal architecture play an essential role in effective recognition of the substrates by activated protein-tyrosine kinases (PTK) and their subsequent signaling functions. Among the various oncogenic PTK-activated pathways, phosphatidylinositol 3-kinase (PI3K)/Akt signaling is the most critical for anchorage-independent survival and growth. The activation of signal transducer and activator of transcription-3 (Stat3) and its function overlap partially with that of the PI3K/Akt in promoting anchorage-independent growth. Among the Rho family guanosine triphosphatases (GTPase), Cdc42, and to some extent Rac1, also appear to be important for promoting anchorage-independent growth.