The model of Tabas and coworkers (52, 53) is revised to incorporate data in this report. Free cholesterol accumulates in macrophage ER membranes, alters their physical properties, inhibits SERCA, and causes ER Ca2+ loss. This activates UPR-CHOP pathway, causes a rise in cytosolic [Ca2+], which amplifies the TLR4-MyD88-JNK pathway, and activates iPLA2β, which associates with mitochondria to facilitate cytochrome c release. In coordination with signals from SRA and TL4 receptor engagement, the combinatorial convergence of multiple events induces apoptosis (53).