Most bacterial cells lead lives of quiet desperation in biofilms, combatting stress; yet, their prevalence attests to their ability to alter gene regulation to cope with myriad insults. Since biofilm bacteria are faced with starvation and other environmental stress (e.g., antibiotics from competitors, oxidative stress from host immune systems), it behooves them to be able to ramp down their metabolism in a highly regulated manner and enter a resting state known as persistence to weather stress. Hence, persister cells are metabolically dormant cells that arise predominantly as a response to stress through elegant gene regulation that includes toxin/antitoxin systems. In this review, an analysis is made of the genetic pathways that lead to persistence, of cell signaling via the interspecies and interkingdom signal indole that leads to persistence, and the means found to date for combatting these cells which are frequently tolerant to a range of antibiotics. Biotechnol. Bioeng. 2016;113: 476-483. (c) 2015 Wiley Periodicals, Inc.