Cyanobacteria, the only known prokaryotes that perform oxygen-evolving photosynthesis, are receiving strong attention in basic and applied research. In using solar energy, water, CO2 and mineral salts to produce a large amount of biomass for the food chain, cyanobacteria constitute the first biological barrier against the entry of toxics into the food chain. In addition, cyanobacteria have the potential for the solar-driven carbon-neutral production of biofuels. However, cyanobacteria are often challenged by toxic reactive oxygen species generated under intense illumination, i.e., when their production of photosynthetic electrons exceeds what they need for the assimilation of inorganic nutrients. Furthermore, in requiring high amounts of various metals for growth, cyanobacteria are also frequently affected by drastic changes in metal availabilities. They are often challenged by heavy metals, which are increasingly spread out in the environment through human activities, and constitute persistent pollutants because they cannot be degraded. Consequently, it is important to analyze the protection against oxidative and metal stresses in cyanobacteria because these ancient organisms have developed most of these processes, a large number of which have been conserved during evolution. This review summarizes what is known regarding these mechanisms, emphasizing on their crosstalk.