Although seagrasses and marine macroalgae (macro-autotrophs) play critical ecological roles in reef, lagoon, coastal and open-water ecosystems, their response to ocean acidification (OA) and climate change is not well understood. In this review, we examine marine macro-autotroph biochemistry and physiology relevant to their response to elevated dissolved inorganic carbon [DIC], carbon dioxide [CO2], and lower carbonate [CO32−] and pH. We also explore the effects of increasing temperature under climate change and the interactions of elevated temperature and [CO2]. Finally, recommendations are made for future research based on this synthesis. A literature review of >100 species revealed that marine macro-autotroph photosynthesis is overwhelmingly C3 (≥ 85%) with most species capable of utilizing HCO3−; however, most are not saturated at current ocean [DIC]. These results, and the presence of CO2-only users, lead us to conclude that photosynthetic and growth rates of marine macro-autotrophs are likely to increase under elevated [CO2] similar to terrestrial C3 species. In the tropics, many species live close to their thermal limits and will have to up-regulate stress-response systems to tolerate sublethal temperature exposures with climate change, whereas elevated [CO2] effects on thermal acclimation are unknown. Fundamental linkages between elevated [CO2] and temperature on photorespiration, enzyme systems, carbohydrate production, and calcification dictate the need to consider these two parameters simultaneously. Relevant to calcifiers, elevated [CO2] lowers net calcification and this effect is amplified by high temperature. Although the mechanisms are not clear, OA likely disrupts diffusion and transport systems of H+ and DIC. These fluxes control micro-environments that promote calcification over dissolution and may be more important than CaCO3 mineralogy in predicting macroalgal responses to OA. Calcareous macroalgae are highly vulnerable to OA, and it is likely that fleshy macroalgae will dominate in a higher CO2 ocean; therefore, it is critical to elucidate the research gaps identified in this review.