Since early work by Wretlind and Schuberth led to the development of a stable and safe intravenous fat emulsion (IFE) using soybean oil (SO) and egg phospholipid emulsifier, IFEs have become a crucial source of essential fatty acids and nonprotein energy in parenteral nutrition. However, largely due to their high ω-6 polyunsaturated fatty acid (PUFA) and phytosterol content, SO IFEs have been associated with complications, including a proinflammatory profile and hypertriglyceridemia, as well as intestinal failure–associated liver disease. Subsequent generations of IFEs have used other sources of triglycerides, including medium-chain triglycerides (MCTs), olive oil (OO), and fish oil (FO), to reduce the SO component. Although these IFEs showed some improvement in complications compared with SO IFE, the quest to develop an IFE with a better side effect profile and beneficial physiologic effects led to the development of a mixed-oil (MO) IFE (Smoflipid; 30% SO, 30% MCTs, 25% OO, and 15% FO) that was recently approved by the Food and Drug Administration. The use of a MO approach is theoretically and intuitively more physiologically similar to normal dietary human consumption. Although the data are from small, short-term trials, MO IFE results thus far have been promising, with some studies showing improved liver function tests, improvement in triglycerides, higher ω-3/ω-6 PUFA ratio, and higher α-tocopherol. Larger long-term studies are needed to ensure these theoretical benefits lead to significant improvement in clinical outcomes.