Thrombus formation is believed to be the major cause of stroke and infarction. Current understanding imposes mechanisms based on leucocyte and platelet activity. However, red blood cells make up a significant part of the clot. An active participation of red blood cells was hypothesised. Cell based methods, namely the patch-clamp technique and observing as well as manipulating optical methods (video-imaging and holographic laser tweezers, respectively) were used to characterise human red blood cells to explore cellular signalling and cellular interactions. Extracellular signalling molecules such as lysophosphatidic acid, prostaglandin E₂ or NMDA can activate cation channels in the red blood cell membrane. The consecutive calcium signal shows a distinct cell to cell variation throughout the red cell population. The calcium signal results in several cellular responses: (i) cell shrinkage due to the Gardos-channel activity, (ii) lipid asymmetry breakdown and phosphatidyl serin exposure to the outer membrane leaflet due to scramblase activity and (iii) irreversible cellular adhesion within individual red blood cells. Although the adhesion mechanism can just be speculated about we can provide an estimation of the adhesion force to be appoximately 100 pN. We provide further evidence derived from single cell experiments for the active participation of red blood cells in thrombotic events. In light of an increasing number of clinical indications, especially under pathophysiologica conditions, such as sickle cell disease, thalassemia or dialysis patients, red blood cells may slowly move into the focus of comprehensive pharmacological strategies for preventing such thrombosis related events such as stroke and cardiac infarction.