Current experiments likely cover only a fraction of all protein-protein interactions. Here, we developed a method to predict SH2-mediated protein-protein interactions using the structure of SH2-phosphopeptide complexes and the FoldX algorithm. We show that our approach performs similarly to experimentally derived consensus sequences and substitution matrices at predicting known in vitro and in vivo targets of SH2 domains. We use our method to provide a set of high-confidence interactions for human SH2 domains with known structure filtered on secondary structure and phosphorylation state. We validated the predictions using literature-derived SH2 interactions and a probabilistic score obtained from a naive Bayes integration of information on coexpression, conservation of the interaction in other species, shared interaction partners, and functions. We show how our predictions lead to a new hypothesis for the role of SH2 domains in signaling.