Hyperglycemia is common in hospitalized patients and associated with adverse clinical outcomes. In hospitalized patients, multiple factors contribute to hyperglycemia, such as underlying medical conditions, pathophysiological stress, and medications. The development of transient insulin resistance is a known cause of hyperglycemia in both diabetic and nondiabetic patients. Though physicians are familiar with common diseases that are known to be associated with insulin resistance, the majority of us rarely come across a case of extreme insulin resistance. Here, we report a case of prolonged course of extreme insulin resistance in a patient admitted with diabetic ketoacidosis (DKA) and acute myocardial infarction (MI). The main purpose of this paper is to review the literature to identify the underlying mechanisms of extreme insulin resistance in a patient with DKA and MI. We will also briefly discuss the different clinical conditions that are associated with insulin resistance and a general approach to a patient with severe insulin resistance.