Cholesterol is an essential lipid for mammalian cells and its homeostasis is tightly regulated. Disturbance of cellular cholesterol homeostasis is linked to atherosclerosis and cardiovascular diseases. A central role in the sensing and regulation of cholesterol homeostasis is attributed to the endoplasmic reticulum (ER). This organelle harbours inactive transcription factors, which sense ER cholesterol levels and initiate transcriptional responses after activation and translocation into the nucleus. Thereupon, these responses enable adaption to high or low cellular cholesterol levels. Besides the abovementioned canonical functions, ER stress—induced by metabolic burden—and the resulting unfolded protein response influence cholesterol metabolism relevant to metabolic disorders. This review summarizes basic as well as recent knowledge on the role of the ER in terms of regulation of cholesterol metabolism.