Antibiotic resistance is expected by the WHO to be the biggest threat to human health before 2050. In this overview, we argue that this prediction may in fact be too optimistic because it is often overlooked that many bacterial infections frequently ‘go under the radar’ because they are difficult to diagnose and characterize. Due to our lifestyle, persistent infections caused by op-portunistic bacteria—well-known or emerging—show increasing success of infecting patients with reduced defense capacity, and often antibiotics fail to be sufficiently effective, even if the bacteria are susceptible, leaving small bacterial populations unaffected by treatment in the patient. The mechanisms behind infection persistence are multiple, and therefore very difficult to diagnose in the laboratory and to treat. In contrast to antibiotic resistance associated with acute infections caused by traditional bacterial pathogens, genetic markers associated with many persistent infections are imprecise and mostly without diagnostic value. In the absence of effective eradication strategies, there is a significant risk that persistent infections may eventually become highly resistant to antibiotic treatment due to the accumulation of genomic mutations, which will transform colonization into persistence.