MOTIVATION: G protein-coupled receptors (GPCRs) play an important role in many physiological systems by transducing an extracellular signal into an intracellular response. Over 50% of all marketed drugs are targeted towards a GPCR. There is considerable interest in developing an algorithm that could effectively predict the function of a GPCR from its primary sequence. Such an algorithm is useful not only in identifying novel GPCR sequences but in characterizing the interrelationships between known GPCRs. RESULTS: An alignment-free approach to GPCR classification has been developed using techniques drawn from data mining and proteochemometrics. A dataset of over 8000 sequences was constructed to train the algorithm. This represents one of the largest GPCR datasets currently available. A predictive algorithm was developed based upon the simplest reasonable numerical representation of the protein's physicochemical properties. A selective top-down approach was developed, which used a hierarchical classifier to assign sequences to subdivisions within the GPCR hierarchy. The predictive performance of the algorithm was assessed against several standard data mining classifiers and further validated against Support Vector Machine-based GPCR prediction servers. The selective top-down approach achieves significantly higher accuracy than standard data mining methods in almost all cases.