Cellulose nanocrystals (CNCs) are naturally occurring, structural material building blocks, which exhibit great potential for future multifunctional nanocomposites due to their high bioavailability, low cost, and impressive mechanical properties. Recent research on CNCs has focused on isolation techniques, crystal morphology, mechanical property characterization, and development of hierarchical materials, including CNC thin films and CNC-based nanocomposites. These studies have revealed that the unique conformation, structure, and surface chemistry of CNCs contribute directly to their outstanding mechanical performance and anisotropic features. To better facilitate their applications in hierarchical, bioinspired materials and exploit the inherent benefits of these biological building blocks, interfacial interactions and mechanics of CNCs with various materials, including other nanocrystals, polymer matrices, and small-molecule solvents, must be explored. This review highlights recent work focusing on the interfacial mechanics of CNCs. We discuss the current progress that has advanced our understanding of their behavior, and future challenges that must be addressed in order to fully exploit the potential of CNCs in engineered materials.