Binding energy hot spots, smaller regions of binding sites that contribute a disproportionate amount to the free energy of binding any ligand, can be determined computationally from ligand-free structures of protein targets. The hot spot structure of a protein target provides very useful information on binding properties. The first application that will be discussed is predicting druggability, i.e., the ability of a site of binding druglike ligands with sufficient affinity. We applied the method to a large set of proteins. Results showed that, because the method is based on the biophysics of binding rather than on empirical parameterization, meaningful information can be gained about classes of proteins and classes of compounds beyond those resembling validated targets and conventionally druglike ligands. In particular, the method identifies targets that, while not druggable by druglike compounds, may become druggable using compound classes such as macrocycles or other large molecules beyond the rule-of-five limit. Second, we show that the hot spots provide crucial insights into the prospects for successful application of fragment-based drug discovery (FBDD), and whether a fragment hit can be advanced into a high affinity ligand. The key factor is the strength of the top ranking hot spot, and how well a given fragment complements it. We show that published data are sufficient to provide a sophisticated and quantitative understanding of how hot spot strength, number and spatial arrangement govern the potential for a surface site to bind to fragment-sized and larger ligands. This improved understanding provides important guidance for the effective application of FBDD in drug discovery.