The ability to assemble nanoscale functional building blocks is a useful and modular way for scientists to design valuable materials with specific physical and chemical properties. Chemists expect multicomponent, heterostructured nanocrystals to show unique electrical, thermal, and optical properties not seen in homogeneous, single-phase nanocrystals. Although researchers have made remarkable advances in heterogeneous nucleation and growth, design of synthetic conditions for obtaining nanocrystals with a target composition and shape is still a big challenge. There are several outstanding issues that chemists need to address before they can successfully carry out the design-based synthesis of multicomponent nanocrystals. For instance, small changes in the reaction parameters, such as the precursor, solvent, surfactant, reducing agent, and the reaction temperature, often result in changes in the structure and chemical composition of the final product. Although scientists do not fully understand the mechanisms underlying the nucleation and growth processes involved in the synthesis of these multicomponent nanocrystals, recent progress in understanding of the thermodynamic and kinetic factors have improved our control over their final structure and chemical composition. In this Account, we summarize our recent advances in understanding of the nucleation and growth mechanisms involved in the solution-based synthesis of multicomponent nanocrystals. We also discuss the various challenges encountered in their synthesis, emphasizing what still needs special consideration. We first discuss the three different nucleation paths from a thermodynamics perspective: amorphous nucleation, crystalline nucleation, and two-step nucleation. Amorphous nucleation and two-step nucleation involve the generation of nonstoichiometric nuclei. We initiate this process mainly by introducing an imbalance in the concentrations of the reduced elements. When the nonstoichiometric nuclei grow, we can add secondary elements to the growing nonstoichiometric nuclei. This leads to either the physical deposition or atomic mixture formation through the diffusion and rearrangement of constituents. The processes of mixture formation and the physical deposition of the secondary constituent element also compete and determine the shape and chemical composition of the final product. If the free energy change by mixture formation is positive (ΔGAB ≥ 0), physical deposition takes place predominantly, and the spreading coefficient (S) determines the structure of the nanocrystals. However, when mixture formation is highly spontaneous (ΔGAB < -ξ), the chemical composition of the final product is usually stoichiometric, and its shape then depends on the size of the primary nanocrystals. When the mixture formation and physical deposition are in competition (-ξ ≤ ΔGAB < 0), as commonly seen for many nanoalloy systems, both the chemical composition and the structure are determined by the size of the primary nanocrystals as well as the degree of mixture formation at the interface of the constituent components. Finally, we discuss the challenges and caveats that one needs to take into account when synthesizing multicomponent nanocrystals.