© 2016 American Society for Reproductive Medicine Objective To summarize the available evidence for the efficacy of various treatments for unexplained infertility. Design Systematic review. Setting Not applicable. Patient(s) Patients aged 18–40 years with unexplained infertility. Intervention(s) Clomiphene citrate, letrozole, timed intercourse, IUI, gonadotropins, IVF, and IVF–intracytoplasmic sperm injection. Main Outcome Measure(s) Clinical pregnancy rate, ongoing pregnancy rate, and live birth rate. Result(s) Thirteen studies with a total of 3,081 patients were identified by systematic search and met inclusion criteria. The available literature demonstrates that expectant management may be comparable to treatment with clomiphene and timed intercourse or IUI. Clomiphene may be more effective than letrozole, and treatment with gonadotropins seems more effective, albeit with significantly higher risk of multiple gestations than either oral agent. On the basis of current data, IVF, with or without intracytoplasmic sperm injection, is no more effective than gonadotropins with IUI for unexplained infertility. Conclusion(s) Adequately powered, randomized controlled trials that compare all of the available treatments for unexplained infertility are needed. Until such data are available, clinicians should individualize the management of unexplained infertility with appropriate counseling regarding the empiric nature of current treatment options including IVF.