Immunosuppression is mandatory after solid organ transplantation between HLA mismatched individuals. It is a lifelong therapy that needs to be closely monitored to avoid under- and over-immunosuppression. For many drugs, pharmacokinetic monitoring has been proven to be beneficial. However, the therapeutic ranges are statistically derived surrogate markers for the effects that cannot predict the individual response of single patients. Better tailored immunosuppression biomarkers are needed that indicate immune activation. T cells are critically involved in organ rejection, and the means to assess their activation state may be promising to individualize immunosuppressive therapies. Activated T cells can be monitored with flow cytometry based on surface molecules that are typically up regulated or with molecules that are cleaved off the cell surface. Among these molecules are the interleukin-2 receptor (CD25); transferrin receptor (CD71); the T cell co-stimulatory molecules CD28, CD69, and CD154 and sCD30, which is a member of the TNF-alpha family. The effect of immunosuppressive drugs on T cell activation can be recorded with indirect cell function assays or by directly monitoring activated T cells in whole blood. Soluble proteins can be measured with immunoassays. This review provides a summary of the experimental and clinical studies investigating the potential of surface molecules as a tool for immune monitoring. It critically discusses the obstacles and shortcomings from an analytical and diagnostic perspective that are currently preventing their use in multicenter trials and clinical routine monitoring of transplant patients.