The function of an individual protein is typically defined by protein-protein interactions orchestrating the formation of large complexes critical for a wide variety of biological processes. Over the last decade the analysis of purified protein complexes by mass spectrometry became a key technique to identify protein-protein interactions. However, mass spectrometry based interactomics is time-consuming and is becoming more prone to identification of false-positive interactors with constantly increasing sensitivity of mass spectrometers. In addition, overexpression of proteins may often yield false-positive interactors while suitable antibodies to pull-down endogenous proteins are often unavailable or might interfere with the binding of interaction partners. To overcome these technical issues, we present a fast and straight-forward approach for analyses of interacting proteins combining a Flp-in single-copy cellular integration system and single-step affinity purification with single-shot mass spectrometry analysis. We applied this protocol to the analysis of the YAP and TAZ interactome. YAP and TAZ are the downstream effectors of the mammalian Hippo tumor suppressor pathway. Our study provides comprehensive interactomes for both, YAP and TAZ and does not only confirm the majority of previously described interactors but, strikingly, revealed uncharacterized interaction partners that affect YAP/TAZ TEAD dependent transcription. Among these newly identified candidates are Rassf8, Thymopoetin and the transcription factors CEBPβ/ and CBFB. In addition, our data allowed insights into complex stoichiometry and uncovered discrepancies between the YAP and TAZ interactomes. Taken together, the stringent approach presented here could help to significantly sharpen the understanding of protein-protein networks.