OBJECTIVE: To emphasize that measurement of a C-peptide level can be critical in the diagnosis and appropriate management of patients with diabetes mellitus. METHODS: We present a series of clinical cases in which glycemic control proved challenging, and we discuss the underlying pathophysiologic features of type 1 versus type 2 diabetes. RESULTS: In a series of 12 illustrative cases, suboptimal control of blood glucose levels in patients with diabetes prompted further investigation. Assessment of C-peptide levels helped determine a precise diagnosis of type 1 or type 2 diabetes, information that was pivotal in choosing treatment options and improving the outcome. These examples show that the age of the patient at the time of diagnosis of diabetes does not necessarily indicate the type of diabetes that is present. CONCLUSION: Clinicians should be aware of the importance of establishing whether patients have type 1 or type 2 diabetes mellitus and the implications of that distinction on the effectiveness of therapeutic strategies.