All extant animals have experienced the same evolutionary time, and the interaction between a species’ evolved physiological traits and their environment is crucial for their success or failure. It is through this species-specific lens that our chapter sought to evaluation the knowledge of invertebrate and agnathan red blood cells in an effort to inform on the evolution of this important cell type. While red blood cells occur only sporadically in invertebrates, it remains true that the presence of red blood cells is an ancestral trait that has been shaped by different evolutionary pressure across different lineages. In broad terms, invertebrate red blood cells are poorly adapted to control the intracellular environment, rarely circulate between the respiratory epithelium and tissue, and often contribute to only a fraction of the overall oxygen consumption of the animals under normal conditions. This is a stark contrast to the red blood cells of the active and migratory lamprey species in which red blood cells are almost solely responsible for transporting oxygen from the respiratory epithelium to the tissues, albeit with several unique characteristics that separate them from gnathostomes. Our chapter will discuss what is known about the functional significance of red blood cells across invertebrate and agnathan species, including where in the body they are found and aspects of their structure, metabolism, and ion transport characteristics, as well as pH and volume regulation. As hemoglobin is a defining feature of red blood cells, we also delve into the characteristics of invertebrate and agnathan hemoglobins, particularly with respect to cooperativity and pH-sensitive oxygen affinity.