High pressure homogenization is a valuable top-down technique for both the small scale and the industrial production of nanoparticles and nanovesicles. The reason for that is its ease of operation, scalability, reproducibility and high throughput. Interestingly, the technique shows a uniquely broad nanomaterial-forming capacity that can process from soft emulsions to brittle crystals. In this chapter, the use of HPH to prepare nanoemulsions was put in parallel to its application in making nanocrystals of different types. The technique appears to be the gold standard for nanoemulsion preparation, but challenges exist in the case of nanocrystals. For example, although HPH fundamentally works by breaking the vesicles/particles, the mechanical properties of the starting crystals are rarely considered during the design of the homogenizing protocols. In the case of emulsions, however, the breakage resistance originated from the system’s viscosity is already well-known for affecting the outcome of the process. A series of examples and discussions are brought together to suggested that structure- and surface-specific characteristics (e.g. molecular arrangement on the crystal facets, surface adhesion, existence of cleavage planes, morphology/shape, particle aspect ratio) are to be incorporated in future studies related to HPH and nanocrystals. This may help in the rational selection of the instrument parameters, but also in understanding the use of HPH in novel technological applications, like self-stabilizing Pickering emulsions and the scalability of complex multicomponent crystal forms like cocrystals.