Affinity-Purification Mass-Spectrometry (AP-MS) provides a powerful means of identifying protein complexes and interactions. Several important challenges exist in interpreting the results of AP-MS experiments. First, the reproducibility of AP-MS experimental replicates can be low, due both to technical variability and the dynamic nature of protein interactions in the cell. Second, the identification of true protein-protein interactions in AP-MS experiments is subject to inaccuracy due to high false negative and false positive rates. Several experimental approaches can be used to mitigate these drawbacks, including the use of replicated and control experiments and relative quantification to sensitively distinguish true interacting proteins from false ones.