About 20% of the cancer incidences worldwide have been estimated to be associated with infections. However, the molecular mechanisms of exactly how they contribute to host tumorigenesis are still unknown. To evade host defense, pathogens hijack host proteins at different levels: sequence, structure, motif, and binding surface, i.e., interface. Interface similarity allows pathogen proteins to compete with host counterparts to bind to a target protein, rewire physiological signaling, and result in persistent infections, as well as cancer. Identification of host-pathogen interactions (HPIs)—along with their structural details at atomic resolution—may provide mechanistic insight into pathogen-driven cancers and innovate therapeutic intervention. HPI data including structural details is scarce and large-scale experimental detection is challenging. Therefore, there is an urgent and mounting need for efficient and robust computational approaches to predict HPIs and their complex (bound) structures. In this chapter, we review the first and currently only interface-based computational approach to identify novel HPIs. The concept of interface mimicry promises to identify more HPIs than complete sequence or structural similarity. We illustrate this concept with a case study on Kaposi’s sarcoma herpesvirus (KSHV) to elucidate how it subverts host immunity and helps contribute to malignant transformation of the host cells.