The need for high-κ gate dielectrics and metal gates in advanced integrated circuits has reopened the door to Ge and III–V compounds as potential replacements for silicon channels, offering the possibility to further increase the performances of complementary metal oxide semiconductor (CMOS) circuits, as well as adding new functionalities. Yet, a fundamental issue related to high-mobility channels in CMOS circuits is the electrical passivation of their interfaces (i.e., achieving a low density of interface defects) approaching state-of-the-art Si-based devices. Here we discuss promising approaches for the passivation of Ge and III–V compounds and highlight insights obtained by combining experimental characterization techniques with first-principles simulations.