Pseudomonas aeruginosa is a metabolically versatile bacterium that can cause a wide range of severe opportunistic infections in patients with serious underlying medical conditions. These infections are characterized by an intense neutrophilic response resulting in significant damage to host tissues and often exhibit resistance to antibiotics leading to mortality. Treatment of persistent infections is additionally hampered by adaptive resistance, due to the growth state of the bacterium in the patient including the microorganism's ability to grow as a biofilm. An array of P. aeruginosa virulence factors counteract host defences and can cause direct damage to host tissues or increase the bacterium's competitiveness. New prevention and treatment methods are urgently required to improve the outcome of patients with P. aeruginosa infections. This review describes the two main types of P. aeruginosa lung infections and provides an overview of the host response and how the genomic capacity of P. aeruginosa contributes to the pathogenesis and persistence of these infections.