Extracellular/intracellular stimuli can influence eukaryotic cell function through organelles that regulate critical signaling pathways. The endoplasmic reticulum (ER), for example, impacts cellular processes including protein synthesis, folding and secretion; amino acid transport; apoptosis; cell proliferation; lipid synthesis across major cell types in response to stimuli such as accumulation of misfolded proteins and glucose deprivation. Dysregulated signaling pathways underlying the ER-mediated processes mentioned above have been linked to disease conditions such as diabetes, obesity, and Alzheimer's disease. Our current understanding, however, lacks a detailed network view that integrates organelle-mediated pathway dysregulation with cellular processes and disease pathogenesis. In this report, we introduce an integrative network biology approach that combines ER-stress response pathways with basic cellular processes using data from peer-reviewed literature. As an example, we apply our systems biology approach to study the role of ER stress in pancreatic β cells under obese diabetic conditions, generate testable hypotheses, and provide novel insights into β-cell pathogenesis.