The selective binding of caffeine to polymers is of interest in developing caffeine-specific sensors. The influence of the nature and quantity of crosslinking agents and functional monomers on the selectivity and binding affinity of a polymer to caffeine is reported. A high binding affinity and selectivity of divinylbenzene (DVB) crosslinked polymers toward caffeine was exhibited by the binding competition of caffeine with several dimethylated and chlorinated xanthines and N-methylated uric acids in aqueous media. To understand the nature of the caffeine-polymer interaction, we performed binding studies with solvents of different polarities and ionic strengths. The binding properties of DVB-based polymers containing different functional monomers were compared with Amberlite((R)) XAD resins. Analytes with hydrophilic and electron-withdrawing groups lowered their binding affinity with the polymer in comparison with caffeine and its dimethylated derivatives. The caffeine-polymer interaction appeared to be predominantly a hydrophobic pi-pi interaction but partly due to the presence of caffeine-specific sites. The reversibility of the caffeine-polymer binding was investigated, and the dissociation constants were approximated to be 27 and 6 mM. Dipole moments of caffeine and related molecules were estimated theoretically and were correlated with their corresponding Err ratio, which is defined as the fraction of caffeine bound to the polymer.