- As the number of effective antibiotics dwindled, antibiotic resistance (AR) became a pressing concern. Some Pseudomonas aeruginosa isolates are resistant to all available antibiotics. In this review, we identify the mechanisms that P. aeruginosa uses to evade antibiotics, including intrinsic, acquired, and adaptive resistance. Our review summarizes many different approaches to overcome resistance. Antimicrobial peptides have potential as therapeutics with low levels of resistance evolution. Rationally designed bacteriophage therapy can circumvent and direct evolution of AR and virulence. Vaccines and monoclonal antibodies are highlighted as immune-based treatments targeting specific P. aeruginosa antigens. This review also identifies promising drug combinations, antivirulence therapies, and considerations for new antipseudomonal discovery. Finally, we provide an update on the clinical pipeline for antipseudomonal therapies and recommend future avenues for research.