Persisters are dormant variants of regular cells that form stochastically in microbial populations and are highly tolerant to antibiotics. High persister (hip) mutants of Pseudomonas aeruginosa are selected in patients with cystic fibrosis. Similarly, hip mutants of Candida albicans are selected in patients with an oral thrush biofilm. These observations suggest that persisters may be the main culprit responsible for the recalcitrance of chronic infectious disease to antimicrobial therapy. Screening knockout libraries has not produced mutants lacking persisters, indicating that dormancy mechanisms are redundant. Toxin/antitoxin (TA) modules are involved in persister formation in Escherichia coli. The SOS response leads to overexpression of the TisB toxin and persister formation. TisB is a membrane-acting peptide that apparently sends cells into dormancy by decreasing the proton motive force and ATP levels. Stress responses may act as general activators of persister formation. Proteins required for maintaining persisters may represent realistic targets for discovery of drugs capable of effectively treating chronic infections.