A wide variety of today’s engineering material systems consist of multiple layered constituents to satisfy varying demands, e.g. thermal barrier- or hard coatings, thermal- or electrical conduction or insulation layers, or diffusion barriers. However, these layers are commonly only of the order of a few hundred nanometers to microns thick, which renders conventional mechanical investigation of interfacial failure quite challenging, especially if plastically deforming constituents are involved. Herein, we present an in situ study of the mechanical deformation of a WTi-Cu model interface, commonly encountered in the microelectronics industry, utilizing transmission scanning electron microscopy. This approach elucidated the interplay between plastic deformation and fracture processes when loading either perpendicular (mode I) or parallel to the interface (mode II). Under mode I purely ductile failure in the Cu phase, exhibiting dislocation slip facilitated void nucleation and coalescence, was observed with an initiation value for dislocation propagation of Jdislocation≈15 J/m2. Mode II loading exhibited nucleation and propagation of an interface crack, with the initiation value for crack extension as Jcrack≈8.8 J/m2. The results are discussed with respect to the frameworks of classical fracture mechanics and dislocation plasticity, providing fundamental insight into the failure behaviour of elastic–plastic interfaces with respect to loading orientation.