Vitamin D and omega-3 fatty acids from fish oil are among the most powerful nutrients for improving overall health, and they are also among the most commonly deficient. EPA and DHA improve a number of cardiovascular risk factors including lowering of atherosclerotic burden, reducing triglyceride levels and blood pressure, and improving platelet and vascular function. Vitamin D has also been shown to modify cardiovascular risk and reduce the risk of several cancers, autoimmune disease, osteoporotic fractures, and overall mortality. EPA and DHA are essential to the resolution of inflammatory processes, as well as tissue repair, by providing the substrates for anti-inflammatory prostaglandins, resolvins and protectins, and vitamin D has recently been shown to have anti-inflammatory effects as well. Omega-3 fatty acids are incorporated into membrane phospholipids, affecting cellular membrane organization, ion permeability, intracellular signalling, gene expression and the activity of membrane-associated proteins. EPA and DHA combined with vitamin D are likely to have synergistic benefits for improving overall wellness, as well as for preventing and treating a wide variety of cardiovascular, inflammatory and autoimmune conditions.