The charge/discharge microstructural conditions that lead to mechanical failure, salt precipitation, and lithium dendrite formation in rechargeable lithium-ion batteries are explored. By starting from high resolution X-ray tomography, three-dimensional representations of porous microstructures from commercially batteries are used to simulate its local electrochemical and chemo-mechanical behavior and identify those microstructural features that will favor failure and heterogeneous lithium nucleation. The analysis demonstrates that spatial variation in porosity, particle roughness and morphology significantly alter the local intercalation kinetics, state of charge, mechanical stability, and dendrite formation. Based on this analysis, the thermodynamic conditions that will enable current density-controlled failure, its macroscopic Weibull statistics, and a overpotential-controlled critical lithium electrodeposit to become energetically favorable are identified. We define several regimes of growth behavior and directly compare them against experimental data to propose: nucleation and growth regimes,  where after a short incubation time nuclei will grow as a result of favored morphological instabilities and localized fields  directly impacting the macroscopic response and long term useful life of the device.