Recent significant advances have been made in the treatment of chronic inflammatory diseases with initiation of the era of biologics. However, an unmet medical need still exists for novel targeted therapies. Compared with biologics, Janus kinase inhibitors (JAKis) are a new drug class of orally administered small molecules that have been shown to efficiently modulate complex cytokine-driven inflammation in preclinical models and human studies. Unfortunately, serious adverse effects have been reported with the first introduced pan-JAKi, tofacitinib. Here, we review tyrosine kinase 2 (TYK2) signaling in the pathophysiology of inflammatory bowel disease (IBD), examine mechanisms of action of selective TYK2 inhibitors (TYK2is), and discuss the potential for these inhibitors in efforts to balance benefits and harms.