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Pseudomonas aeruginosa is a highly successful opportunistic pathogen that displays intrinsic multidrug resistance and has a tremendous capacity to acquire further resistance mechanisms. During chronic infection, the bacterium can form a protective biofilm therefore reducing the efficacy of existing antibiotics. P. aeruginosa also harbors an impressive range of virulence factors, many of which are controlled by the quorum-sensing system. Several novel therapeutics are under investigation such as those directed against biofilm formation and quorum-sensing systems along with bacteriophages and immunotherapies. Recent advances in next-generation sequencing and comparative genomics have opened the door to a new wave of smart drug design that could revolutionize P. aeruginosa treatment options.