Several biological agents have been added to our armamentarium of treatment options for moderate to severely active inflammatory bowel diseases, and this number is expected to only increase in the near future. With our growing understanding of disease mechanisms and pharmacokinetics, we are now able to target several mechanisms of action to achieve key endpoints (steroid-free remission and mucosal healing) associated with improved long-term disease-related outcomes. In this context, concerns arise regarding the optimal positioning of currently available biologics and key biologics in development. In this review, we will discuss the currently available evidence for comparative effectiveness of biological agents approved for the use in moderate to severely active inflammatory bowel diseases, with a focus on practical considerations to be made when using these agents in practice. We will further review novel biological agents and small molecule inhibitors in development and discuss future opportunities through which providers may personalize treatment decisions to achieve optimal treatment outcomes.