Gabapentin (GP) and pregabalin (PB) are structurally related compounds and their predominant mechanism of action is the inhibition of calcium currents via high-voltage-activated channels containing the a2d-1 subunit. A2delta ligands are approved for the treatment of pain of diabetic neuropathy and post-herpetic neuralgia in adults and as adjunctive therapy of partial seizures in children. Recently, pregabalin has been approved for treatment of anxiety disorders in Europe. Besides their already approved indications both drugs are promising treatment options for a number of different serious and debilitating diseases, as fibromyalgia, neuropathic pain of spinal cord injury, hot flushes, and essential tremor. In the present review, the unique mechanism of action of the above drugs is critically analyzed and evidence for their future use is provided. Gabapentin and pregabalin can be treatment options for these disorders, however, a clear comparison between the two drugs can not be performed, since there is no direct comparison study. The most common side effects are dizziness and somnolence which are also the most frequent reasons for withdrawal. Recommendations for future studies should include assessment of ideal titration period for GP and PB to reduce incidence of somnolence and dizziness and increase tolerability, cost-effectiveness and dose-response analysis of PB and GP and direct comparison of the two drugs.