Short bowel syndrome (SBS) is a rare but complex disorder resulting from extensive intestinal resection, vascular diseases, or inflammatory bowel disease, associated with serious morbidity and mortality, significant health care costs, and a reduced quality of life. Managing malabsorption, diarrhea, and fluid-electrolyte imbalances in these patients is always challenging. Medications including antisecretory, antimotility, and luminally active agents play a major role in controlling high stool output, minimizing fluid and electrolyte losses and enhancing intestinal absorption. Antisecretory medication, such as proton pump inhibitors and somatostatin analogs, decrease gastrointestinal secretions, reducing diarrhea and dehydration. Opioids and opioid receptor agonists, which inhibit intestinal smooth muscle contraction, are frequently used to enhance absorption by slowing intestinal transit. Luminally active agents, such as bile acid sequestrants and oral rehydration solutions, optimize nutrient absorption and fluid balance. Emerging therapies, such as GLP-2 analogs, show promise in promoting intestinal adaptation and reducing reliance on parenteral nutrition. The chapter underscores the importance of individualized treatment plans to optimize outcomes, manage adverse effects, and improve patients’ quality of life.