Most essential cellular functions are accomplished by dynamic macromolecular assemblies comprised of least one enzymatic component surrounded by non-enzymatic moieties that enforce the timing, location and specificity of the complex function. In the case of transcription, for example, transcriptional activators direct the assembly of the RNA polymerase II holoenzyme at specific gene promoters at particular time points; once the polymerase is engaged, the complex disassembles as transcription initiates. This is accomplished through protein-protein interactions (PPIs) that are dynamic and, in some cases, short-lived. Mis-regulation of activator-transcriptional machinery assembly events is at the heart of human diseases from cancer to neurodegenerative disorders and the PPIs that direct these dynamic processes are critical for probe development and for therapeutic targeting. Despite their importance and their prevalence, activator-transcriptional machinery PPIs are historically all but impossible for small molecule modulation and are often classified as 'undruggable'. The challenge is multi-variable: the binding partners often have significant disorder and are thus difficult to characterize structurally alone or in complex; the surface area of the area of the interactions are considerably larger than protein-ligand interactions and the strengths of the interactions are modest. Here we will discuss two new strategies for the discovery of small molecule modulators of activator-transcriptional machinery PPIs, strategies that have produced molecules with unique potency and specificity profiles.