•Protein-protein interaction (PPI) mapping at proteome-scale provides a global view of cellular organization and function.•Of the various methods for identifying PPIs, only three techniques can be easily scaled to survey the entire proteome.•Computational efforts allow for the prediction of PPIs, as well as finer mapping by modeling PPIs.•The collection and integration of proteome-scale PPI data has many applications, including exploration of disease mechanisms and evolution.•Future mapping efforts will move beyond static or simplified maps by incorporating quantitative and dynamic features. Proteins effect a number of biological functions, from cellular signaling, organization, mobility, and transport to catalyzing biochemical reactions and coordinating an immune response. These varied functions are often dependent upon macromolecular interactions, particularly with other proteins. Small-scale studies in the scientific literature report protein–protein interactions (PPIs), but slowly and with bias towards well-studied proteins. In an era where genomic sequence is readily available, deducing genotype–phenotype relationships requires an understanding of protein connectivity at proteome-scale. A proteome-scale map of the protein–protein interaction network provides a global view of cellular organization and function. Here, we discuss a summary of methods for building proteome-scale interactome maps and the current status and implications of mapping achievements. Not only do interactome maps serve as a reference, detailing global cellular function and organization patterns, but they can also reveal the mechanisms altered by disease alleles, highlight the patterns of interaction rewiring across evolution, and help pinpoint biologically and therapeutically relevant proteins. Despite the considerable strides made in proteome-wide mapping, several technical challenges persist. Therefore, future considerations that impact current mapping efforts are also discussed.