Detection and quantification of analytes in clinical settings (e.g., routine blood testing), at home (e.g., glucose monitoring), in the field (e.g., environmental monitoring, war fighter protection, homeland security), and in the factory (e.g., worker health, beverage and food safety) is exceedingly challenging. Chemical sensors and biosensors have attracted considerable attention because of their perceived ability to meet these challenges. Chemical sensors exploit a recognition element in concert with a transduction strategy. When the recognition element is biological (e.g., antibody, aptamer, enzyme), the sensor is termed a biosensor. There is substantial literature on biosensing; however, there are compelling reasons for developing inexpensive, robust, and reusable alternatives for the expensive or unstable biorecognition elements. This Account summarizes recent research on designing and producing analyte-responsive materials based on molecularly imprinted xerogels.