Certain infectious diseases caused by pathogenic bacteria are typically chronic in nature. Potentially deadly examples include tuberculosis, caused by Mycobacterium tuberculosis, cystic fibrosis-associated lung infections, primarily caused by Pseudomonas aeruginosa, and candidiasis, caused by the fungal pathogen Candida albicans. A hallmark of this type of illness is the recalcitrance to treatment with antibiotics, even in the face of laboratory tests showing the causative agents to be sensitive to drugs. Recent studies have attributed this treatment failure to the presence of a small, transiently multidrug-tolerant subpopulation of cells, so-called persister cells. Here, we review our current understanding of the role that persisters play in the treatment and outcome of chronic infections. In a second part, we offer a perspective on the development of anti-persister therapies based on genes and mechanisms that have been implicated in persistence over the last decade.