Disturbances to the balance of protein synthesis, folding and secretion in the endoplasmic reticulum (ER) induce stress and thereby the ER stress signaling (ERSS) response, which alleviates this stress. In this Commentary, we review the emerging idea that ER stress caused by abnormal physiological conditions and/or mutations in genes that encode client proteins of the ER is a key factor underlying different developmental processes and the pathology of diverse diseases, including diabetes, neurodegeneration and skeletal dysplasias. Recent studies in mouse models indicate that the effect of ERSS in vivo and the nature of the cellular strategies induced to ameliorate pathological ER stress are crucial factors in determining cell fate and clinical disease features. Importantly, ERSS can affect cellular proliferation and the differentiation program; cells that survive the stress can become 'reprogrammed' or dysfunctional. These cell-autonomous adaptation strategies can generate a spectrum of context-dependent cellular consequences, ranging from recovery to death. Secondary effects can include altered cell-extracellular-matrix interactions and non-cell-autonomous alteration of paracrine signaling, which contribute to the final phenotypic outcome. Recent reports showing that ER stress can be alleviated by chemical compounds suggest the potential for novel therapeutic approaches.