Pseudomonas aeruginosa is a major, but opportunistic, respiratory pathogen, which rarely infects healthy individuals, mainly due to the barrier effect of the human airway epithelium (HAE). This review explores the interaction of P . aeruginosa with HAE and the progression of the infection. The basolateral part of the epithelium, which includes the basolateral membrane of the epithelial cells and the basement membrane, is inaccessible in normal tight epithelia with intact junctions. We highlight how P . aeruginosa exploits weaknesses in the HAE barrier to gain access to the basolateral part of the epithelium. This access is crucial to initiate respiratory infection and is mainly observed in the injured epithelium, in repairing or chronically remodeled epithelium, and during extrusion of senescent cells or cell multiplication during normal epithelium renewal. The subsequent adhesion of the bacteria and cytotoxic action of virulence factors, including the toxins delivered by the type 3 secretion system (T3SS), lead to retractions and cell death. Eventually, P . aeruginosa progressively reaches the basement membrane and propagates radially through the basal part of the epithelium to disseminate using twitching and flagellar motility.