By the mid 1980's, it was clear that the transforming activity of oncogenic Src 
was linked to the activity of its tyrosine kinase domain and attention turned to 
identifying substrates, the putative next level of control in the pathway to 
transformation. Among the first to recognize the potential of 
phosphotyrosine-specific antibodies, Parsons and colleagues launched a risky 
shotgun-based approach that led ultimately to the cDNA cloning and functional 
characterization of many of today's best-known Src substrates (for example, 
p85-Cortactin, p110-AFAP1, p130Cas, p125FAK and p120-catenin). Two decades and 
over 6000 citations later, the original goals of the project may be seen as 
secondary to the enormous impact of these protein substrates in many areas of 
biology. At the request of the editors, this review is not restricted to the 
current status of the substrates, but reflects also on the anatomy of the 
project itself and some of the challenges and decisions encountered along the 
way.