Drug therapy may become difficult when a significant amount of the small intestine is resected, as happens in patients with a short small bowel. Drug absorption from the gastrointestinal tract is altered in these patients; however, this effect is variable in patients and differs with each drug. Literature regarding clinical outcomes of normal or alternative administration routes in patients with a short small bowel is limited. We explored what is written about the normal absorption of commonly used drugs and what difference the resection of different but substantial parts of the small intestine makes. Changes in the gastrointestinal tract after resection of >50% of the small intestine causes malabsorption of macronutrients and micronutrients, and may alter the drug absorption process. The metabolic activity of the abundantly present intestinal lactobacilli can also affect the enteral drug absorption in patients with short small bowel as this results in the production of lactic acid, gaseous CO(2), ethanol and an increased bile acid deconjugation. Accelerated intestinal luminal transit time causes a reduction in absorption of certain antimicrobial agents, digoxin, hydrochlorothiazide, ciclosporin, cimetidine, mesalazine (5-aminosalicylic acid), oral contraceptives and levothyroxine. Gastric hypersecretion and lack of sufficient contact time with the intestinal mucosa in patients with short small bowel leads to insufficient absorption of drugs such as omeprazole. Successful treatment with warfarin, tricyclic antidepressants, metronidazole, fluconazole, procainamide, sotalol and pindolol are reported in several studies. Many different factors cause this variability in drug absorption in such patients. Monitoring the serum drug concentration in these patients may ease dealing with the management problems.