The flexible ligand docking problem is divided into two subproblems: pose/conformation search and scoring function. For successful virtual screening the search algorithm must be fast and able to find the optimal binding pose and conformation of the ligand. Statistical analysis of experimental data of bound ligand conformations is presented with conclusions about the sampling requirements for docking algorithms. eHiTS is an exhaustive flexible-docking method that systematically covers the part of the conformational and positional search space that avoids severe steric clashes, producing highly accurate docking poses at a speed practical for virtual high-throughput screening. The customizable scoring function of eHiTS combines novel terms (based on local surface point contact evaluation) with traditional empirical and statistical approaches. Validation results of eHiTS are presented and compared to three other docking software on a set of 91 PDB structures that are common to the validation sets published for the other programs.