This chapter delves into the pivotal role of vertebrate red blood cells (RBCs) in the regulation of gas transport, focusing on oxygen (O2) and carbon dioxide (CO2) exchange. Through a comparative physiological approach, it examines the fundamental principles of O2 transport, emphasizing the crucial role of hemoglobin in enhancing O2-binding capacity and facilitating efficient delivery to tissues. The chapter further examines the unique adaptations of RBCs across different vertebrate taxa, highlighting how environmental conditions and evolutionary pressures have shaped their functional characteristics. Special attention is given to the mechanisms of O2 binding and release, including the effects of cooperativity and O2 affinity, and how these processes are modulated in response to varying physiological demands. The chapter also covers the traditional and alternative pathways of CO2 transport and excretion, with a particular focus on the distinct strategies employed by extant agnathans. Moreover, it explores the dynamic nature of RBC metabolism, showcasing how RBCs actively participate in and regulate gas transport through metabolic adaptations. These adaptations are essential for managing O2 loading and unloading in response to physiological demands, underscoring the RBCs’ role beyond being mere passive carriers of gases. Through this comprehensive analysis and by highlighting recent technological advances and pivotal studies, this analysis provides new insights into the complex interplay between RBC properties, gas transport mechanisms, and evolutionary adaptations that enable vertebrates to meet their respiratory and metabolic requirements efficiently. The chapter concludes by discussing future research directions, underscoring the importance of understanding these physiological processes in the face of environmental changes and their implications for vertebrate survival.