Computational conformational sampling underpins many aspects of small molecule modeling and design in pharmaceutical work. This work examined in detail the widely distributed LigPrep/ConfGen software suite and the conformational models it produces for drug-like compounds. We also compare LigPrep/ConfGen to MOE and Catalyst. Tests of the conformational sampling protocols included the reproduction of known bioactive structures of ligands, characterization of the size, coverage and diversity of the output conformational models, and relative computation times. The present tests will help the user to make informed choices among the predefined ConfGen protocols (Very fast, Fast, Intermediate, and Comprehensive), and the adjustable input parameters. The parameters governing the initial compound preparation (LigPrep) and the subsequent conformational sampling were explored. This analysis has led to a new protocol called "ConfGen Optimized", which improves upon the predefined protocols. ConfGen Optimized is computationally tractable and reproduced 80% of the bioactive structures within 1 A, versus 66% for the default ConfGen Fast protocol. We also addressed the issue of the reproduction of compact/folded bioactive structures by ConfGen. It involved the compilation of a new set of 50 folded diverse drug-like bioactive structures. This indicates that heuristics penalizing folded conformers hinder reproduction of some binding modes. Overall, ConfGen offers great flexibility of use and provides a valuable addition to the molecular modeling toolbox.