Inflammatory bowel disease (IBD) is difficult to diagnose, and differentiating between ulcerative colitis (UC) and Crohn's disease (CD) can be challenging. Overlapping symptoms of UC and CD often delay diagnosis, despite availability of endoscopic, radiologic, and histologic tools. This delay in diagnosis is quite common in clinical practice, which may also delay initiation of appropriate treatment. Abnormal immune responses found in IBD have led to the use of serum biomarkers (eg, anti-Saccharomyces cerevisiae antibody [ASCA], perinuclear antineutrophil cytoplasmic antibody [pANCA], antibodies to flagellin [anti-CBir1]) to improve diagnostic confidence in IBD. These biomarkers are beginning to be used to stratify patients with UC and CD according to disease phenotype and risk of complications. Associations between quantity and quality of immune reactivity and severe disease phenotypes are increasingly evident. This suggests that serologic panels of multiple IBD biomarkers can be used to identify the relative risk of progression to complicated disease behaviors, and that this information may ultimately impact therapeutic decisions. This review discusses the diagnostic process and challenges in IBD, with emphasis on the role that serologic markers may play in addressing these challenges.