Thrombospondins are secreted, extracellular matrix (ECM) proteins that are upregulated in the heart and other tissues in response to ischemic injury and myocardial stress. Roles for thrombospondins after they are secreted have been examined in a variety of disease models, including myocardial pathology. However, a recent study published in the journal Cell by Lynch et al shifts this paradigm by focusing on roles for intracellular thrombospondins; these authors showed that thrombospondin-4 (Thbs4) can function from within cells to protect the heart by enhancing adaptive aspects of the endoplasmic reticulum (ER) stress response that are mediated by activating transcription factor 6, ATF6. Although this study was carried out in the cardiac context, the results add to our understanding of protein folding and quality control in all tissues. Moreover, the findings underscore the potential widespread therapeutic benefit of enhancing adaptive responses that are regulated by ATF6.