The growing availability of novel structures for several G protein-coupled receptors (GPCRs) has provided new opportunities for structure-based drug design of ligands against this important class of targets. Here, we report a systematic analysis of the accuracy of docking small molecules into GPCR structures and homology models using both rigid receptor (Glide SP and Glide XP) and flexible receptor (Induced Fit Docking; IFD) methods. The ability to dock ligands into different structures of the same target (cross-docking) is evaluated for both agonist and inverse agonist structures of the A2A receptor and the β1- and β2-adrenergic receptors. In addition, we have produced homology models for the β1-adrenergic, β2-adrenergic, D3 dopamine, H1 histamine, M2 muscarine, M3 muscarine, A2A adenosine, S1P1, κ-opioid, and C-X-C chemokine 4 receptors using multiple templates and investigated the ability of docking to predict the binding mode of ligands in these models. Clear correlations are observed between the docking accuracy and the similarity of the sequence of interest to the template, suggesting regimes in which docking can correctly identify ligand binding modes.