In the past decade, several new therapies with different mechanisms of action have been approved for the management of moderate to severe Crohn’s disease. However, there is limited guidance on optimal positioning of agents as first- or second-line therapies because of the absence of head-to-head trials. Furthermore, given the lack of comparative studies, treatment guidelines have provided limited insight. In this review, we discuss data on key treatment attributes, comparative efficacy and safety, factors predictive of response to each agent, and propose an algorithm for positioning therapies for the management of patients with low-risk and high-risk Crohn’s disease.