Ocean acidification (OA) research seeks to understand how marine ecosystems and global elemental cycles will respond to changes in seawater carbonate chemistry in combination with other environmental perturbations such as warming, eutrophication, and deoxygenation. Here, we discuss the effectiveness and limitations of current research approaches used to address this goal. A diverse combination of approaches is essential to decipher the consequences of OA to marine organisms, communities, and ecosystems. Consequently, the benefits and limitations of each approach must be considered carefully. Major research challenges involve experimentally addressing the effects of OA in the context of large natural variability in seawater carbonate system parameters and other interactive variables, integrating the results from different research approaches, and scaling results across different temporal and spatial scales.