Aptamer-ligand binding events, involving small molecule targets, at a surfactant-laden aqueous/liquid crystal (LC) interface were found to trigger a LC reorientation that can be observed in real-time using polarized light. The response was both sensitive and selective: reorientation was observed at target concentrations on the order of the aptamer dissociation constant, but no response was observed in control experiments with target analogues. Circular dichroism and resonance energy transfer experiments suggested that the LC reorientation was due to a conformational change of the aptamer upon target binding. Specifically, under conditions where aptamer-ligand binding induced a conformational change from a relaxed random coil to more intricate secondary structures (e.g., double helix, G-quadruplex), a transition from planar to homeotropic LC orientation was observed. These observations suggest the potential for a label-free LC-based detection system that can simultaneously respond to the presence of both small molecules and nucleic acids.