Personalized treatments with molecularly targeted agents are considered new and heading towards a bright future in medical oncology. The development of imatinib was a landmark and its clinical and commercial success revolutionized many new developments in this area. Molecular targeted therapies require strict patient selection to identify those who may benefit. Novel targeted (personalized) therapies with antibodies such as trastuzumab have proven, undoubtedly, their added value in the clinic for large patient populations. Targeted therapies with “small molecules” are most successful, however, in “single defect”, rare cancers such as Philadelphia chromosome positive chronic myeloid leukemia. Resistance and side effects are limitations in their clinical application. Cancer is, in most cases, a multifactorial disease and multi-targeted agents or combinations may be required to obtain cancer cures finally. We present our personal view on the current developments in this field.