Heterogeneous interfaces are pivotal in numerous nanoscale devices and applications. First-principles approaches based on quantum mechanics and atomistic structures provide critical insights into structure-property relationships, enabling the informed design of materials and devices. Accurate first-principles methods must reliably capture many-body effects, i.e., electron-electron interactions, which significantly influence system properties compared to the predictions from models using free or noninteracting electrons. In this Perspective, we survey a few computational tools in this context and attempt to be forward looking by discussing the current challenges and emerging research opportunities. We examine diverse manifestations of many-body effects across several domains: geometries and reaction barriers (total-energy properties), orbital energy levels and band alignments (one-particle properties), and optical excited states (two-particle properties).