Cell surface receptors and their interactions fundamentally determine physiological and pathological signaling. Despite its clinical relevance, the Immunoglobulin Superfamily (IgSF) remains remarkably uncharacterized and many receptors are orphan. We present the first systematic extracellular protein map, the IgSF Interactome. Using a high throughput technology to interrogate most single transmembrane receptors for binding to 445 IgSF proteins, we identify over 500 interactions, 85% previously unreported, and confirm new interactions for immune checkpoints and orphan proteins using orthogonal assays. Our study reveals functionally related protein communities and the landscape of dysregulated receptor-ligand crosstalk in cancer, including selective loss-of-function for tumor-associated mutations. Investigation of the IgSF Interactome in a large cohort of cancer patients enrolled in a phase 2 clinical trial reveals expression signatures of interacting proteins associated with poor response to immunotherapy. The IgSF Interactome represents a unique resource to fuel biological discoveries and a framework for understanding the functional organization of the surfaceome during homeostasis and disease, ultimately informing therapeutic development.