Fibromyalgia is a chronic pain disease whose clinical symptomatology also includes different symptom domains: fatigue, sleep disturbances, morning stiffness, dyscognition, and psychological distress. These associated symptoms usually vary in frequency and intensity from patient to patient. Because the efficacy of monotherapy is limited, more severely affected patients frequently require drug combinations. There is, however, scarce scientific information concerning the benefits and risks of such combinations. To date, only ten studies investigating the efficacy and tolerability of two-drug combinations have been published; some of these studies are old and/or studied drugs that are now known to be of little or no interest in fibromyalgia management. Thus, when polytherapy is considered, therapeutic decisions must be based on data from monotherapy trials and a sound knowledge of the pharmacological profile of each drug. Well-designed clinical trials exploring specific drug combinations selected on the basis of potential additive or synergistic effects should be performed.