In the past decades, great strides have been made in the synthesis of hybrid nanocrystals (HNCs) consisting of two or more disparate subunits (such as metals and/or semiconductors) joined through nanointerfaces, which are intriguing due to their exceptional functionalities that cannot be achieved by single-component nanosystems. The promising and versatile applications of these HNCs are closely dependent on the structural and electronic properties of the nanointerface between subunits. This is because the compatibility of the lattice structures between subunits not only determines the synthetic accessibility and growth mechanisms of the HNCs on the thermodynamic basis but also influences their interfacial characteristics (atomic arrangement, lattice mismatch-induced strain or defects), configurations, crystallinity, and the synergistic interplay of different subunits at the nanoscale. As a result, nanointerface chemistry has attracted intense scientific endeavors worldwide and spurred the rapid development of the lattice-mismatch-directed precise synthesis. This review gives an overview of the main strategies developed for delicate design and fabrication of core-shell HNCs under different degrees of lattice mismatch (from 0.2% to larger than 50%), including epitaxial seeded growth, nanoscale cation exchange, cation exchange-facilitated nonepitaxial growth, etc. Moreover, as for the core-shell HNCs with small (<5%) or moderate lattice mismatch (∼5-20%), the significance of the lattice-strain control at the nanointerface in maneuvering their functions toward desired applications are discussed in detail. Regarding the core-shell HNCs with large lattice mismatch (>20%), the challenges in precise synthesis, the promising solutions enabled by cation exchange-facilitated nonepitaxial growth, and the enhanced applications of the resulting HNCs with strain-free nanointerface are elaborated. We conclude with a personal perspective on the significance and urgency of fully harnessing the effects of lattice mismatch to further advance the science of synthesis and application of HNCs.