Location of functional binding pockets of bioactive ligands on protein molecules is essential in structural genomics and drug design projects. If the experimental determination of ligand-protein complex structures is complicated, blind docking (BD) and pocket search (PS) calculations can help in the prediction of atomic resolution binding mode and the location of the pocket of a ligand on the entire protein surface. Whereas the number of successful predictions by these methods is increasing even for the complicated cases of exosites or allosteric binding sites, their reliability has not been fully established. For a critical assessment of reliability, we use a set of ligand-protein complexes, which were found to be problematic in previous studies. The robustness of BD and PS methods is addressed in terms of success of the selection of truly functional pockets from among the many putative ones identified on the surfaces of ligand-bound and ligand-free (holo and apo) protein forms. Issues related to BD such as effect of hydration, existence of multiple pockets, and competition of subsidiary ligands are considered. Practical cases of PS are discussed, categorized and strategies are recommended for handling the different situations. PS can be used in conjunction with BD, as we find that a consensus approach combining the techniques improves predictive power.