Drug resistance still impedes successful cancer chemotherapy. A major goal of early concepts in individualized therapy was to develop in vitro tests to predict tumors’ drug responsiveness. We have developed an in vitro short-term test based on nucleic acid precursor incorporation to determine clinical drug resistance. This test detects inherent and acquired resistance in vitro and transplantable syngeneic and xenografted tumors in vivo. In several clinical trials, clinical resistance was predictable with more than 90% accuracy, while drug sensitivity was detected with less accuracy (~60%). Remarkably, clinical cross-resistance to numerous drugs (multidrug-resistance, broad spectrum resistance) was detectable by a single compound, doxorubicin, due to its multifactorial modes of action. The results of our predictive test were in good agreement with predictive assays of other authors. As no predictive test has been established as yet for clinical diagnostics, the identification of sensitive drugs may not reach sufficiently high reliability for clinical routine. We propose a rethinking of the chemosensitivity concept. Instead, predictive in vitro tests may reliably identify drug-resistant tumors. The clinical consequence imply to subject resistant tumors not to chemotherapy, but to other new treatment options such as antibody therapy, adoptive immune therapy, hyperthermia, gene therapy etc. The high accuracy to predict resistant tumors may be exploited to develop new strategies for individualized cancer therapy. This new concept bears the potential of a revival of predictive tests for personalized medicine.