This article introduces a systems biology model of the psycho-immune-neuroendocrine (PINE) network. It provides a comprehensive synthesis of the network of biological mechanisms which link major depressive disorder (MDD) with several diseases including hypertension, atherosclerosis, coronary heart disease (CHD), cerebrovascular accident (CVA) and type 2 diabetes. The first part of this article provides an overview of concepts such as the PINE physiome and pathome, as well as the application of a systems biology framework to explain the significant reciprocal associations of MDD with the above named medical illnesses. The second part describes the normal physiological pathways of immune mechanisms, the hypothalamic-pituitary-adrenal (HPA) axis, autonomic pathways and central nervous system function, which form the PINE physiome. The third section describes how homeostasis of the PINE physiome is disrupted by chronic stress, on a background of genetic and developmental diathesis factors, resulting in a network of pathophysiological pathways called the PINE pathome. MDD, CHD, type 2 diabetes, CVA, hypertension and atherosclerosis can act to maintain the PINE network in a stable pathological state. This article presents comprehensive topographical maps of both the PINE physiome and the PINE pathome. Implications of the model and the importance of adopting a systems approach to understanding the relationship between these diseases is discussed in the last section, including the possibility of novel treatments for MDD and areas of future research.