EGSITE2 represents a substantial advance in a long series of methods for calculating receptor site models given only specific binding data. Compared to our most recently reported technique, EGSITE [Schnitker et al. J. Comput.-Aided Mol. Des. 1997, 11, 93-110] the user no longer has to simplify the structures of the molecules in the training set by clustering the atoms into a few superatoms. The only remaining source of subjectivity is the user's choice of compounds for the training set, which can be surprisingly few in number. Then EGSITE2 automatically produces typically several different models that explain the observed binding without outliers. The models are remarkably simple but have substantial predictive power for any sort of test compound, with an estimation of the uncertainty of the prediction. Validation of the method is reported for four standard test cases: triazines and pyrimidines binding to dihydrofolate reductase, steroids binding to corticosteroid-binding globulin and to testosterone-binding globulin, and peptides binding to angiotensin-converting enzyme.