In steatotic hepatocytes, intracellular Ca2+ homeostasis is substantially altered compared to normal. Decreased Ca2+ in the endoplasmic reticulum (ER) can lead to ER stress, an important mediator of the progression of liver steatosis to nonalcoholic steatohepatitis, type 2 diabetes, and hepatocellular carcinoma. Store-operated Ca2+ channels (SOCs) in hepatocytes are composed principally of Orai1 and STIM1 proteins. Their main role is the maintenance of adequate Ca2+ in the lumen of the ER. In steatotic hepatocytes, store-operated Ca2+ entry (SOCE) is substantially inhibited. This inhibition is associated with a decrease in Ca2+ in the ER. Lipid-induced inhibition of SOCE is mediated by protein kinase C (PKC) and may involve the phosphorylation and subsequent inhibition of Orai1. Experimental inhibition of SOCE enhances lipid accumulation in normal hepatocytes incubated in the presence of exogenous fatty acids. The antidiabetic drug exendin-4 reverses the lipid-induced inhibition of SOCE and decreases liver lipid with rapid onset. It is proposed that lipid-induced inhibition of SOCE in the plasma membrane and of SERCA2b in the ER membrane leads to a persistent decrease in ER Ca2+, ER stress, and the ER stress response, which in turn enhances (amplifies) lipid accumulation. A low level of persistent SOCE due to chronic ER Ca2+ depletion in steatotic hepatocytes may contribute to an elevated cytoplasmic-free Ca2+ concentration leading to the activation of calcium-calmodulin kinase II (CaMKII), decreased lipid removal by autophagy, and insulin resistance. It is concluded that lipid-induced inhibition of SOCE plays an important role in the progression of liver steatosis to insulin insensitivity and hepatocellular carcinoma.