Genetically engineered T cells expressing chimeric antigen receptors (CAR) present a new treatment option for patients with cancer. Recent clinical trials of B cell leukemia have demonstrated a response rate of up to 90%. However, CAR cell therapy is frequently accompanied by severe side effects such as cytokine release syndrome and the development of target cell resistance. Consequently, further optimization of CARs to obtain greater long-term efficacy and increased safety is urgently needed. Here we high-light the various efforts of adjusting the intracellular signaling domains of CARs to these major requirements to eventually obtain high-level target cell cytotoxicity paralleled by the establishment of longevity of the CAR expressing cell types to guarantee for extended tumor surveillance over prolonged periods of time. We are convinced that it will be crucial to identify the molecular pathways and signaling requirements utilized by such 'efficient CARs' in order to provide a rational basis for their further hypothesis-based improvement. Furthermore, we here discuss timely attempts of how to: i) control 'on-tumor off-target' effects; ii) introduce Signal 3 (cytokine responsiveness of CAR cells) as an important building-block into the CAR concept; iii) most efficiently eliminate CAR cells once full remission has been obtained. We also argue that universal systems for the variable and pharmacokinetically-controlled attachment of extracellular ligand recognition domains of choice along with the establishment of 'off-the-shelf' cell preparations with suitability for all patients in need of a highly-potent cellular therapy may become future mainstays of CAR cell therapy. Such therapies would have the attraction to work independent of the patients' histocompatibility make-up and the availability of functionally intact patient's cells. Finally, we summarize the evidence that CAR cells may obtain a prominent place in the treatment of non-malignant and auto-reactive T and B lymphocyte expansions in the near future, e.g., for the alleviation of autoimmune diseases and allergies. After the introduction of red blood cell transfusions, which were made possible by the landmark discoveries of the ABO blood groups by Karl Landsteiner, and the establishment of bone marrow transplantation by E. Donnall Thomas to exchange the entire hematopoietic system of a patient suffering from leukemia, the introduction of patient-tailored cytotoxic cellular populations to eradicate malignant cell populations in vivo pioneered by Carl H. June, represents the third major and broadly applicable milestone in the development of human cellular therapies within the rapidly developing field of applied biomedical research of the last one hundred years.