The purpose of this review was to compare the efficacy and safety of biologics, immunomodulators, corticosteroids, and aminosalicylates in the treatment of Crohn’s disease. We searched MEDLINE(®) (1966 through June 2011), Embase(®) (1974 through June 2011), and the Cochrane Central Register of Controlled Trials (Issue 2, 2011). Two reviewers independently reviewed titles, abstracts, and articles, and included English-language articles that reported on induction or maintenance of remission in placebo-controlled or head-to-head randomized controlled trials. We also included observational studies with a comparison group if they reported on the safety of treatment. Two reviewers extracted study information using standardized forms and independently assessed study quality. Efficacy was measured by induction and maintenance of remission. Remission was defined using the Crohn’s Disease Activity Index, mucosal healing, the absence of Crohn’s disease hospitalizations or surgeries, reduction of steroids, fistula healing, and patient-reported outcomes. A difference of 10 percentage points in the outcome between treatment groups was considered clinically meaningful. The safety outcomes of interest were mortality, occurrence of lymphomas and other cancers, infections, infusion- and injection-site reactions, and bone fractures for adults and children. Growth was an additional safety concern for children. We included 136 studies involving 148,733 patients. Twenty-three percent of trials directly compared different treatment strategies. The majority of trials excluded patients with mild disease and those with a history of surgical resection. The majority of trials allowed patients to take other Crohn’s disease treatments during the trial. For adults, infliximab and 6-methyl-prednisolone were consistently favored over placebo across the induction and maintenance outcomes. Natalizumab and azathioprine were favored over placebo across the maintenance outcomes. Other comparisons either did not have more than one outcome reported or had inconsistent results. The quality of the safety evidence was poor due to poor reporting of the methods in trials and poor confounding control in observational studies, and no strong signals of harm were identified. For children, the strength of evidence was low or insufficient to support the efficacy of any medication to induce or maintain remission. No pediatric study reported on serious adverse events such as mortality, lymphoma, or other cancers. Measuring the efficacy of medications using multiple outcomes, infliximab and 6-methyl-prednisolone induce and maintain remission in adults with Crohn’s disease. Natalizumab and azathioprine maintain remission. Comparing Crohn’s disease medications directly using pragmatic clinical trials will help to understand the effectiveness of medications in clinical practice using outcomes other than the Crohn’s Disease Activity Index.