Both biological agents and immunosuppressants are standard treatments in inflammatory bowel disease (IBD) and are frequently used in combination. Although this combination can increase therapeutic efficacy and help to prevent immunogenicity, concerns about the risk of adverse effects - particularly lymphoma - have been raised. IBD are obviously highly complex diseases, with many possible clinical scenarios, and there is no a universal treatment applicable to all patients. In this report we address this issue in a narrative review consisting of three parts. First, we provide a historical overview of the use of immunosuppressants and biological agents in IBD. Secondly, we review the available evidence, with both efficacy and safety considered in separate analyses. Thirdly, we propose different ways of using these drugs in the distinct clinical scenarios, both in Crohn's disease and in ulcerative colitis. Although the evidence is thoroughly reviewed, the main perspective is that of the practicing clinician.