As type 2 diabetes has reached pandemic levels affecting nearly 370 million people worldwide, it is critical to understand the cellular processes that influence this disease. Insulin resistance, or the inability of normal levels of insulin to achieve the normal effect, is a hallmark of type 2 diabetes and metabolic syndrome. When going from the fasted to the fed state, insulin binds to the ubiquitously expressed insulin receptor to activate downstream signaling, which regulates many cellular actions such as glucose, lipid, and protein metabolism. At the level of the organism, insulin’s effect on glucose and lipid metabolism occurs primarily through actions on liver, skeletal muscle, and adipose tissue. The various proteins and isoforms that positively and negatively modulate the insulin-signaling cascade ensure a proper response to feeding. However, these regulators of insulin signaling can be disrupted in a variety of ways in response to disease states such as obesity, inflammation, or even during the aging process and contribute to insulin resistance. Understanding the processes by which insulin signaling is affected in response to these disease states is critical to the discovery of new treatments to prevent diabetes, metabolic syndrome, and their complications.