Inflammatory bowel diseases (IBDs) are chronic disabling diseases with significant morbidity. A deregulated immune response towards the intestinal microbiota is thought to play an important role in the pathogenesis of IBD, and thus biological therapies targeting key molecules such as cytokines have been designed. Several anti-TNF-α agents are currently being used to treat Crohn's disease and ulcerative colitis. Although these molecules dramatically improved the treatment of patients, side effects and the development of antidrug antibodies limits their application. There is thus an urgent need for alternative approaches to decrease inflammation and limit immunogenicity. Small neutralizing molecules, active immunization, gene silencing, selective transcription inhibitors and delivery of agents through the oral route are some of the currently developed strategies to meet these needs. In parallel, neutralizing antibodies targeting other pathways of the immune system have been developed and tested. Antibodies targeting IL-12/IL-23 pathways, and proinflammatory cytokines such as IFN-γ, IL-17A, IL-2 and IL-6 often showed an initial promising result, but for none of these agents efficacy has unequivocally been established. Administration of the regulatory cytokines IL-10 and IL-11 also failed to induce reproducible clinical effects. This article focuses on the anti-TNF therapies and the current challenges with monoclonal antibody therapies, discusses the innovative strategies targeting cytokine pathways to decrease inflammation in the bowel, and summarizes the recently developed agents neutralizing proinflammatory cytokines.