With recent advances in computational modeling and in situ experiment technologies, there have been increased efforts to apply these approaches to understand microscopic mechanisms dictating deformation mechanics. In this talk, I will present our recent studies that combine in situ electron microscopy and diffraction experiments with crystal plasticity and atomistic simulations for gaining a deeper understanding of microscopic deformation mechanics. For example, we have combined in situ synchrotron X-ray diffraction experiments with crystal plasticity simulations to investigate microscale residual stresses in additively manufactured stainless steel. We have also combined in situ transmission electron microscopy experiments and atomistic simulations to study the effects of atomic structures and elemental distributions on achieving the unusual mechanical properties of high-entropy alloys. In addition, we have used this approach to reveal the grain boundary deformation atom by atom, step by step, thus uncovering the unexpected grain boundary sliding mechanisms in real time.