Glycemic goals and the therapies used to achieve them must be individualized for each patient based on several factors, one of the more important being coexisting conditions such as renal disease, liver disease, and cardiovascular disease. The potential to lower hemoglobin A1c and the possible long-term benefits of diabetes treatments must be balanced with safety issues, adverse effects, tolerability, ease of use, long-term adherence, and expense. The American Association of Clinical Endocrinologists and the American Diabetes Association have addressed these concerns by developing treatment guidelines to maximize efficacy and safety in the majority of patients with type 2 diabetes. Other organizations, including the American Medical Directors Association and the American Geriatric Society, have also published guidelines for diabetes management for patients in long-term care facilities. This review discusses the safety profiles of antidiabetic drugs, and the special treatment needs with respect to these drugs for patients with diabetes and comorbidities such as renal disease, liver disease, and cardiovascular disease.