The initial CHIVAS-M75 Streptococcus pyogenes pharyngitis human challenge study has delivered a clinically relevant human experimental infection model to support early vaccine proof of concept evaluation and advance understanding of interactions between this highly adapted co-evolved pathogen and its only natural host. I will review the critical steps that preceded CHIVAS-M75, discuss the clinical trial findings, and touch on the wide array of immunology and microbiology studies drawing on samples collected in the initial trial. Recalling the aphorism that, ‘All models are wrong, but some are useful,’ I will discuss the strengths and limitations of S. pyogenes human challenge studies, making the case that human models can have a useful strategic and scientific impact even though they cannot reproduce natural S. pyogenes diversity (the aim is not to build a better mouse). I will introduce plans for forthcoming randomised human challenge trials to evaluate vaccines and inform development of improved long-acting penicillin formulations. Finally, I will consider possibilities to broaden the scope of S. pyogenes human challenge studies to address longstanding points of frustration (and fascination) – key knowledge gaps that have persisted despite more than a century of in vitro and animal studies.