EGF receptor (EGFR) and c-Src are the prototypes that individually represent the receptor and nonreceptor tyrosine kinases respectively. Accumulated evidence reveals the association between EGF-activated EGFR and c-Src that leads to activation of both kinases. Importantly, their mutual interaction is required for many EGFR-mediated cellular functions including proliferation, migration, survival and EGFR endocytosis. Interestingly, activation of c-Src and its association with transactivated EGFR is also observed in cells stimulated with non-EGF agonists. This review will not only discuss the structure, function and regulation of these two tyrosine kinases, but also will summarize our current knowledge of the molecular mechanisms depicting the cellular events that require their participation.