The persistence of Pseudomonas aeruginosa in chronic infections extends beyond the issue of antibiotic resistance. A critical, yet unresolved question is why antibiotics fail to eradicate all infecting bacteria, despite P. aeruginosa often being clinically susceptible. This highlights the need for a comprehensive understanding of persistence mechanisms, which we consider to be directly rooted in the host-pathogen interactions and are frequently overlooked. We propose that host adaptation and alteration may play a fundamental role in the long-term persistence of P. aeruginosa. Elucidating these complex interactions has profound clinical implications, but it requires advanced and innovative model systems that accurately replicate host-pathogen dynamics.