In the past decade, we have witnessed an explosion in the availability of high-resolution structural information that sheds light on the binding of diverse classes of ligands to both soluble proteins and integral membrane receptors. From orthosterics to allosterics, from tiny fragments to enormous rule-breakers, we know more than ever about how ligands bind. However, the ability to accurately predict binding free energies has lagged behind, significantly limiting the utility of this structural information. The good news is that in the past few years there has been a breakthrough in ligand binding free energy prediction. I will summarize the evidence and suggest ways to effectively deploy this new capability