Publisher Summary This chapter discusses the energy landscape separating the unbound from the bound state of protein–protein interactions. Specific protein–protein interactions provide a major part of the basic organization of living cells. The structure of a protein complex embeds the information of the relative mutual organization of two proteins in a frozen state while the affinity allows analysis of the equilibrium thermodynamics of the interaction. Analysis of the kinetics of association and dissociation in solution or within membranes allows for characterizing the landscape in more detail. Single-point mutation analysis has often resulted in perplexing results, which are difficult to simulate using computation. This can be attributed to the cooperative effect of the binding of a group of residues, as is the case in protein–protein interfaces, and to potential structural changes resulting from mutations. This cooperativity is explained in terms of the modular architecture of binding sites. Compared to interaction in solution, anchoring of proteins into the membrane severely changes the energetic landscapes of protein–protein interaction. While the long-range interactions formed during association are a global feature of the protein, the architecture of the interface is modular, with the individual modules being cooperative within themselves but additive between modules.