One of the major obstacles to pursue the discovery of small molecule inhibitors targeting protein–protein interactions is the flat nature of their interface. X-Ray structures have indeed shown that a large part of the interaction area is buried with atoms closely packed together, implying a lack of available cavities for small molecule binding. Yet, it has become clear that some protein–protein interfaces have a well-defined compact area, commonly referred to as a hot spot, that plays a major role in the affinity of the interaction. These hot spots define potential targets for the development of small molecule protein–protein interaction inhibitors (SMPPIIs). In this review we discuss the interactions between viral and host proteins that have the potential for the future development of SMPPIIs. In light of the current anti-HIV therapy a short overview of protein–protein interactions that may serve as targets for novel drugs is provided. Our hypothesis will exemplify and discuss the interaction between HIV-1 integrase and its cellular cofactor LEDGF/p75, which, as evidenced by crystallography and site directed mutagenesis, displays favourable properties needed for the development of interaction inhibitors.