AbstractAntibiotic tolerance—the ability of bacteria to survive for an extended time in the presence of bactericidal antibiotics—is an understudied contributor to antibiotic treatment failure. Herein, I review the manifestations, mechanisms, and clinical relevance of tolerance to cell wall–active (CWA) antibiotics, one of the most important groups of antibiotics at the forefront of clinical use. I discuss definitions of tolerance and assays for tolerance detection, comprehensively discuss the mechanism of action of β‐lactams and other CWA antibiotics, and then provide an overview of how cells mitigate the potentially lethal effects of CWA antibiotic–induced cell damage to become tolerant. Lastly, I discuss evidence for a role of CWA antibiotic tolerance in clinical antibiotic treatment failure.