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The whole blood model is a powerful method to determine the immediate inflammatory reactions towards foreign objects in general. This review focuses on the use of a lepirudin based whole blood model for evaluating microspheres relevant in cell transplantation applications. This whole blood model can be regarded as a holistic model with readouts from cross-talks between leukocytes, complement, most of the coagulation components and fibrinolysis. A major advantage of this model is the possibility of evaluating a panel of different microspheres under identical conditions, and also the possibility of comparing reaction patterns between species. This model is a valuable tool for gaining a mechanistic understanding by selected readouts (as complement and coagulation activation products, cytokines, cell-surface receptors, protein adsorption, cell-attachment), and by use of inflammatory blocking agents (inhibitors). The whole blood model is put in the context of today’s knowledge about inflammatory systems, discussed according to biocompatibility and biotolerability terms and finally discussed according to its ability to predict the outcome of transplanted microspheres in an in vivo environment. This is a submitted manuscript of an article available at EurekaSelect via http://www.eurekaselect.com/112574/article