Shear failure of the interfacial regions of CrN/Cu/Si and CrN/Ti/Si ceramic-coating/metal-adhesion-layer/substrate systems was measured quantitatively and observed concurrently through instrumented compression of cylindrical micro-pillars in-situ a scanning electron microscope. Results indicate that shear failure of the interfacial region occurred in two stages: an initial shear deformation of the entire metal interlayer followed by an unstable shear-off close to the metal/ceramic interface. The shear-off is suggested to be concomitant with the metal/ceramic interface going from being “locked”, with no relative displacement between materials on the two sides of the interface, to being “unlocked”, with significant relative displacements. Density functional theory and molecular dynamics studies on a related metal/ceramic interface, Ti/TiN, showed that a weak interaction plane exists in the metal layer near the chemical interface in a coherent Ti/TiN structure. Consequently, the free energy and theoretical shear strength of the semi-coherent Ti/TiN interface is found to depend on the physical location of the misfit dislocation network (MDN). The minimum energy and strength of the interface occur when the MDN is near, but not at the chemical interface. The relevance of the present work to other metal/ceramic interfaces is discussed.