Detachment of epithelial cells from the basement membrane (BM) induces apoptosis, a phenomenon now widely known as anoikis. Studies in mammary and intestinal epithelial cells have shown that the loss of attachment to the BM rapidly triggers reversible proapoptotic events from which the cells can recover if they reattach within a certain period. Thus, cells seem to be transiently protected from the initial detachment-induced proapoptotic events. The molecular mechanisms underlying such transient protection against anoikis are unknown. In this paper, we present evidence indicating that detachment of intestinal epithelial cells triggers a transient, yet significant increase in the activity of the tyrosine kinases c-Src and c-Fyn, and that this activation of Src-family kinases (SFK) contributes to the transient protection against anoikis in these cells. The protective signals from SFK are mediated by the PI3K pathway, and caveolin-1. In addition, we show that the MEK1-ERK1/2 pathway acts in a synergistic manner with SFK to protect intestinal epithelial cells from anoikis.