Short bowel syndrome (SBS) significantly alters the pharmacokinetic and pharmacodynamic profiles of many drugs due to reduced absorptive surface, altered gastrointestinal motility, pH changes, and compromised enterohepatic circulation. This chapter explores the unique challenges of drug absorption, distribution, metabolism, and excretion in patients with SBS. It reviews how intestinal anatomy, resection type, and remnant bowel function affect drug bioavailability and response. The relevance of the Biopharmaceutical Classification System (BCS), common drug classes affected, and recommendations for alternative routes or formulations are discussed. Limited evidence from small studies highlights the need for therapeutic drug monitoring and individualized pharmacotherapy. The integration of pharmacokinetic and pharmacodynamic principles is essential to ensure effective and safe medication use in this complex patient population.