Leukocytes, platelets, and endothelial cells play a major role in atherosclerosis and coronary heart disease (CHD). Infiltration of intima by leukocytes and macrophages is one of the earliest events to occur in atherosclerosis, whereas leukocytosis is known to be associated with a greater cardiovascular risk. It is well documented that a close interaction occurs between platelets, leukocytes and endothelial cells. This cross talk among these three types of cells ultimately determines the initiation and progression of atherosclerosis and the occurrence of CHD. Under normal conditions, endothelial cells produce adequate amounts of prostaglandin E1 (PGE1), prostacyclin (PGI2), lipoxins (LXs), resolvins, and protectins from polyunsaturated fatty acids; and nitric oxide (NO) from L-arginine such that the proinflammatory and pro-atherosclerotic events induced by hemodynamic forces, hyperlipidemia, hypertension, smoking, hyperglycemia, hyperhomocysteinemia, and oxidant stress are abrogated. Pro-atherosclerotic and pro-inflammatory stimuli enhance the expression of nuclear factor-κB (NF-κB), VCAM-1, ICAM-1, PECAM, IL-1, IL-6, and MCP-1 in endothelial cells, leukocytes and platelets; and enhance the production of pro-inflammatory eicosanoids TXA2, PGE2, PGF2α, LTs, and other PGs, TXs, and LTs, free radicals (including myeloperoxidase) and UCP (uncoupling proteins) by endothelial cells, platelets, and leukocytes in atherosclerosis-susceptible regions that initiate and accelerate atherosclerosis. These events can be prevented and atherosclerosis process is arrested by the production of adequate amounts of PGE1, PGI2, PGI3, LXs, resolvins, protectins, NO, and anti-inflammatory cytokines such as IL-4, IL-10, TGF- β by endothelial cells, provided there are adequate stores of respective precursors of various PUFAs and L-arginine and their respective enzymes. This suggests that under physiological conditions a delicate balance is maintained between proand anti-inflammatory and pro and anti-atherosclerotic factors. When this delicate balance is tilted more towards proatherosclerotic and pro-inflammatory factors, atherosclerosis and CHD occurs.