Prevention of the initiation of biofilm formation is the most important step for combating biofilm-associated pathogens, as the ability of pathogens to resist antibiotics is enhanced 10 to 1000 times once they form biofilms. Genes essential to bacterial growth in the planktonic state are potential targets to treat biofilm-associated pathogens. However, the biofilm formation capability of strains with mutations in these essential genes needs to be evaluated, as the pathogen might form biofilms before it is eliminated. In order to address this issue, this work proposes a systems-biology approach to identify gene targets that are essential for the bacterial metabolism in the planktonic state but do not induce biofilm formation when they are inactivated. The proposed approach was applied to identify target genes to treat Pseudomonas aeruginosa infections. It is interesting to find that the inhibition of most essential planktonic-growth genes might induce the formation of biofilms while the inhibition of most non-essential genes might not. Four essential planktonic-growth genes, i.e., lysC, cysH, adk, and galU, constitute gene targets to treat P. aeruginosa. All four of these genes have been experimentally suggested as potential drug targets for their crucial role in the survival or virulence of P. aeruginosa.