There are at least four mechanisms whereby the nutrient vitamins A, C, D, and E may be related to the processes that impede or give rise to OA. These nutrient vitamins have major roles in modulating oxidative stress, participating in immune responses, and contributing to cell differentiation. There is a substantial need to understand the contribution of these nutrients to OA, because they may provide important insight into ameliorating the initiation and progression of the disease. Simultaneously, greater understanding will add rationality to an area of potential intervention that is often based on anecdote. Investigation will be complex; there is the need to select appropriate systems. Typical animal model systems used in the study of OA are inappropriate because most animals can synthesize ascorbic acid. There is the need to disaggregate, as much as possible, the numerous subsets of OA and the plethora of processes that contribute to that heterogeneity. Certainly, there is the need to recognize the interdependency of the actions of each of these nutrients at the cellular level. Furthermore, humans rarely consume these nutrients as independent products. For example, watermelon is a primary source of both ascorbic acid and beta-carotene. Failure to address these complexities denies the scientist the opportunity to advance our understanding of health and disease processes. More importantly, failure to address these complexities denies the person with OA the opportunity to address his or her own health.