Free Calcium (Ca²⁺) is an important and universal signalling entity in all cells, red blood cells included. Although mature mammalian red blood cells are believed to not contain organelles as Ca²⁺ stores such as the endoplasmic reticulum or mitochondria, a 20,000-fold gradient based on a intracellular Ca²⁺ concentration of approximately 60 nM vs. an extracellular concentration of 1.2 mM makes Ca²⁺-permeable channels a major signalling tool of red blood cells. However, the internal Ca²⁺ concentration is tightly controlled, regulated and maintained primarily by the Ca²⁺ pumps PMCA1 and PMCA4. Within the last two decades it became evident that an increased intracellular Ca²⁺ is associated with red blood cell clearance in the spleen and promotes red blood cell aggregability and clot formation. In contrast to this rather uncontrolled deadly Ca²⁺ signals only recently it became evident, that a temporal increase in intracellular Ca²⁺ can also have positive effects such as the modulation of the red blood cells O₂ binding properties or even be vital for brief transient cellular volume adaptation when passing constrictions like small capillaries or slits in the spleen. Here we give an overview of Ca²⁺ channels and Ca²⁺-regulated channels in red blood cells, namely the Gárdos channel, the non-selective voltage dependent cation channel, Piezo1, the NMDA receptor, VDAC, TRPC channels, Ca_V2.1, a Ca²⁺-inhibited channel novel to red blood cells and i.a. relate these channels to the molecular unknown sickle cell disease conductance P_sickle. Particular attention is given to correlation of functional measurements with molecular entities as well as the physiological and pathophysiological function of these channels. This view is in constant progress and in particular the understanding of the interaction of several ion channels in a physiological context just started. This includes on the one hand channelopathies, where a mutation of the ion channel is the direct cause of the disease, like Hereditary Xerocytosis and the Gárdos Channelopathy. On the other hand it applies to red blood cell related diseases where an altered channel activity is a secondary effect like in sickle cell disease or thalassemia. Also these secondary effects should receive medical and pharmacologic attention because they can be crucial when it comes to the life-threatening symptoms of the disease.