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Antibiotic resistance in <i>Pseudomonas aeruginosa</i> remains one of the most challenging phenomena of everyday medical science. The universal spread of high-risk clones of multidrug-resistant/extensively drug-resistant (MDR/XDR) clinical <i>P. aeruginosa</i> has become a public health threat. The <i>P. aeruginosa</i> bacteria exhibits remarkable genome plasticity that utilizes highly acquired and intrinsic resistance mechanisms to counter most antibiotic challenges. In addition, the adaptive antibiotic resistance of <i>P. aeruginosa</i>, including biofilm-mediated resistance and the formation of multidrug-tolerant persisted cells, are accountable for recalcitrance and relapse of infections. We highlighted the AMR mechanism considering the most common pathogen <i>P. aeruginosa</i>, its clinical impact, epidemiology, and save our souls (SOS)-mediated resistance. We further discussed the current therapeutic options against MDR/XDR <i>P. aeruginosa</i> infections, and described those treatment options in clinical practice. Finally, other therapeutic strategies, such as bacteriophage-based therapy and antimicrobial peptides, were described with clinical relevance.