Microstructurally-induced failure mechanisms in crystalline materials with coincident site-lattice (CSL) high angle grain boundaries (GBs) have been investigated. A multiple-slip rate-dependent crystalline constitutive formulation that is coupled to the evolution of mobile and immobile dislocation densities and specialized computational schemes have been developed to obtain a detailed understanding of the interrelated physical mechanisms that result in material failure. A transmission scalar has also been introduced to investigate slip-rate transmission, blockage and incompatibility at the GB. The combined effects of high angle GB misorientation, mobile and immobile dislocation densities, strain hardening, geometrical softening, localized plastic strains, and slip-rate transmission and blockage on failure evolution in face centered cubic (f.c.c.) crystalline materials have been studied. Results from the present study are consistent with experimental observations that single dislocation pile-ups result in a transgranular failure mode for the ∑9 CSL GB, and that symmetric double dislocation pile-ups result in an intergranular failure mode for the ∑17b CSL GB.