Over the past decade, the therapeutic armamentarium for inflammatory bowel disease (IBD) has substantially expanded with the incorporation of multiple classes of advanced therapies. Currently, in addition to tumor necrosis factor-α inhibitors, the therapeutic arsenal for IBD includes anti-integrin agents, interleukin (IL)-12/23p40 and IL-23p19 antibodies, Janus kinase inhibitors, and sphingosine 1-phosphate receptor modulators. Although advances in IBD pharmacotherapy have enabled disease remission and improved control of intestinal inflammation in many individuals previously considered clinically 'intractable', they have also increased the complexity of decision-making related to the initial positioning and sequencing of therapies in the heterogeneous clinical presentations of IBD. Until molecular and genetic markers capable of predicting therapeutic responses become available in practice, the choice of initial and subsequent therapy in individuals with IBD is based on factors including disease severity, phenotype, risk of complications, comorbidities, extraintestinal manifestations, and the balance between efficacy, safety, convenience, and access. This review explores the factors that influence treatment decisions regarding initial therapy selection and sequencing across IBD scenarios, offering practical tips for personalizing therapy based on the safety and efficacy of advanced treatments and the individual's risk of disease- or therapy-related adverse outcomes.