Molecular imprinting is a facile method to create guest-complementary binding sites in a cross-linked polymeric network. When performed within cross-linked micelles, the resulting molecularly imprinted nanoparticles (MINPs) exhibited an extraordinary ability to distinguish subtle structural changes in the guest, including the shift of a hydrophilic or hydrophobic group by 1 carbon and addition of a single methylene/methyl group. A high surface-cross-linking density prior to core-cross-linking was key to the high-fidelity imprinting, enhancing both the binding affinity of the imprinted micelle for the template and selectivity among structural analogues. Whereas the imprinted site closely complemented the hydrophilic surface anchoring group and rigid hydrophobic aromatic core, it was expanded significantly for a conformationally mobile small group (i.e., methoxy).