A decade ago, we described a new approach to discover next generation adjuvants, identifying small-molecule immune potentiators (SMIPs) as Toll-like receptor (TLR)7 agonists. We also optimally formulated these drugs through adsorption to aluminum salts (alum), allowing them to be evaluated with a range of established and early-stage vaccines. Early proof-of-concept studies showed that a TLR7 agonist (TLR7a)-based SMIP, when adsorbed to alum, could perform as an effective adjuvant for a variety of different antigens, in both small and large animals. Studies in rodents demonstrated that the adjuvant enhanced immunogenicity of a recombinant protein-based vaccine against Staphylococcus aureus, and also showed potential to improve existing vaccines against pertussis or meningococcal infection. Extensive evaluations showed that the adjuvant was effective in non-human primates (NHPs), exploiting a mechanism of action that was consistent across the different animal models. The adjuvant formulation (named AS37) has now been advanced into clinical evaluation. A systems biology-based evaluation of the phase I clinical data with a meningococcal C conjugate vaccine showed that the AS37-adjuvanted formulation had an acceptable safety profile, was potent, and activated the expected immune pathways in humans, which was consistent with observations from the NHP studies. In the intervening decade, several alternative TLR7 agonists have also emerged and advanced into clinical development, such as the alum adsorbed TLR7/8 SMIP present in a widely distributed COVID-19 vaccine. This review summarizes the research and early development of the new adjuvant AS37, with an emphasis on the steps taken to allow its progression into clinical evaluations.