Controlling polymorphism, the ability of a compound to adopt more than one solid-state structure, often relies on empirical manipulations of conditions such as solvent, temperature, and mode of crystallization. Despite a growing interest in nanocrystalline formulations, however, the influence of crystal size on polymorph formation and stability is largely unexplored. Nanocrystals of pimelic acid, HO2C(CH2)n-2 CO2H (n = 7), glutaric acid (n = 5), suberic acid (n = 8), and coumarin (1, 2-benzopyrone) in nanometer-scale pores of controlled pore glass (CPG) beads and hexagonally ordered cylindrical pores of poly(cyclohexylethylene) (p-PCHE) monoliths exhibit size-dependent polymorphism and thermotropic behavior because of the physical constraints imposed by the dimensions of the pores. Pimelic acid, suberic acid, and coumarin also exhibit heretofore unknown polymorphs, denoted δ-pimelic acid, β-suberic acid, and β-coumarin, in CPG with pore sizes < 23 nm and p-PCHE with pore diameters < 40 nm. The melting points of the confined crystals decrease monotonically with decreasing pore size, and the enantiotropic phase behavior of bulk glutaric acid and suberic acid switches to monotropic when confined within the nanoscale pores of CPG and p-PCHE. Collectively, these results reveal that nanometer-scale size confinement can alter crystallization outcomes and affect polymorph stability compared with bulk crystallization. Moreover, crystallization in very small pores can lead to the discovery of new polymorphs that otherwise would not be detected using conventional screening methods.