The pancreas is a centralized organ vital for whole body metabolic control. Recent advances in the field of metabolism have reinforced its importance for orchestrating endocrine hormone secretion in response to several nutrients including glucose, lipids and amino acids, in addition to hormones and inflammatory signals. Cell types within the pancreas, in particular the insulin-producing β cells, control nutrient breakdown and energy production and are essential to maintain not only efficient hormone secretion, but also cell integrity, survival, and the ability to sense and adapt to changing metabolic environments. The present review highlights recent research advances on how glucolipotoxicity, mitochondrial dysfunction, and systemic inflammation affects pancreatic metabolism, and how new technologies and more advanced research models are improving our ability to study this organ system. Taken together, careful characterization and understanding of the importance of nutrient metabolism within this important, yet complex organ, will help us to better understand pathologies intimately associated with the pancreas and possibly discover new and more effective therapeutic strategies.