The rise of antibiotic failure poses a severe threat to global health. There is growing concern that this failure is not solely driven by stable antibiotic resistance but also by a subpopulation of transiently non-growing, antibiotic tolerant bacteria. These ‘persisters’ have been proposed to seed relapsing infections, an important clinical outcome of treatment failure — although definitive evidence for this direct link remains elusive. Recent advances in the field have revealed the complex nature of intra-host persisters which drive their high adaptability through biosynthetic activity. These features of persisters contribute to evolution of antimicrobial resistance and modulation of host immune responses, despite clinically efficacious treatment.