Following sequencing and assembly of the human genome, the preferred methods for identification of new drug targets have changed dramatically. Modern tactics such as genome-wide association studies (GWAS) and deep sequencing are fundamentally different from the pharmacology-guided approaches used previously, in which knowledge of small molecule ligands acting at their cellular targets was the primary discovery engine. A consequence of the ‘target-first, pharmacology-second’ strategy is that many predicted drug targets are non-enzymes, such as scaffolding, regulatory or structural proteins, and their activities are often dependent on protein–protein interactions (PPIs). These types of targets create unique challenges to drug discovery efforts because enzymatic turnover cannot be used as a convenient surrogate for compound potency. Moreover, it is often challenging to predict how ligand binding to non-enzymes might affect changes in protein function and/or pathobiology. Thus, in the postgenomic era, targets might be strongly implicated by molecular biology-based methods, yet they often later earn the designation of ‘undruggable’. Can the scope of available targets be widened to include these promising, but challenging, non-enzymes? In this review, we discuss advances in high-throughput screening (HTS) technology and chemical library design that are emerging to deal with these challenges.