Experimental and epidemiologic data have confirmed that undernutrition or overnutrition during critical periods of life can result in metabolic dysfunction, leading to the development of obesity, hypertension, and type 2 diabetes, later in life. These studies have contributed to the concept of the developmental origins of health and disease (DOHaD), which involves metabolic programming patterns. Beyond the earlier phases of development, puberty can be an additional period of plasticity, during which any insult can lead to changes in metabolism. Impaired brain development, associated with imbalanced autonomous nervous system activity due to metabolic programming, is pivotal to the creation of pathophysiology. Excess glucocorticoid exposure, due to hypothalamic–pituitary–adrenal axis deregulation, is also involved in malprogramming in early life. Additionally, the pancreatic islets appear to play a decisive role in the setup and maintenance of these metabolic dysfunctions as key targets of metabolic programming, and epigenetic mechanisms may underlie these changes. Moreover, studies have indicated the possibility that deprogramming renders the islets able to recover their functioning after malprogramming. In this review, we discuss the key roles of the pancreatic islets as targets of malprogramming; however, we also discuss their roles as important targets for the treatment and prevention of metabolic diseases.