Patients with cystic fibrosis are at risk of developing infections with multidrug-resistant (MDR) pathogens, particularly Pseudomonas aeruginosa. Thus, there has been widespread interest in using antimicrobial agents in combination to expand the antimicrobial spectrum, prevent the emergence of resistance, reduce toxicity and provide synergistic activity. There are multiple methodologies for synergy testing, but checkerboard dilution assays and multiple combination bactericidal testing have been used most often for cystic fibrosis isolates. To date, synergy testing has been advocated to guide treatment for MDR strains of P. aeruginosa associated with a pulmonary exacerbation for which conventional testing does not reveal susceptibility to two agents from different classes of antibiotic. Synergy testing has also been advocated for isolates from patients failing to respond to therapy for treatment of a pulmonary exacerbation or from patients with substantial drug allergies for whom antibiotic choices are limited.