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Over the past decade, the study of protein interaction networks (PINs) has shed light on the organizing principles of living cells. However, PINs have been mostly mapped in one single condition. We outline three of the most promising avenues of investigation in this field, namely the study of first, how PINs are rewired by mutations and environmental perturbations; secondly, how inter-species interactions affect PIN achitectures; thirdly, what mechanisms and forces drive PIN evolution. These investigations will unravel the dynamics and condition dependence of PINs and will thus lead to a better functional annotation of network architecture. One major challenge to reach these goals is the integration of PINs with other cellular regulatory networks in the context of complex cellular phenotypes., (Copyright © 2013 Elsevier Ltd. All rights reserved.)