The systematic identification of all protein-protein interactions that take place in an organism (the 'interactome') is an important goal in modern biology. The nematode Caenorhabditis elegans was one of the first multicellular models for which a proteome-wide interactome mapping project was initiated. Most Caenorhabditis elegans interactome mapping efforts have utilized the yeast two-hybrid system, yielding an extensive binary interactome, while recent developments in mass spectrometry-based approaches hold great potential for further improving our understanding of protein interactome networks in a multicellular context. For example, methods like co-fractionation, proximity labeling, and tissue-specific protein purification not only identify protein-protein interactions, but have the potential to provide crucial insight into when and where interactions take place. Here we review current standards and recent improvements in protein interaction mapping in C. elegans.