Ever since the beginning of work on The Cancer Genome Atlas in 2005, attempts have accumulated to target mutated molecular structures in order to control the proliferation and spread of malignant cells. Generally, tamoxifen, which has been with us since the 1970s, is considered the first drug targeting a molecular structure, thus heralding the beginning of precision medicine. This, however, has only evolved after the identification of appropriate targets an abundance of which not only has been identified but also contributed to our understanding of the biology of malignancies and their frequent subdivision into subentities. The agnostic registration of TRK (tropomyosin receptor kinase) fusion-directed treatments, but also the recognition of such mutations as BRAFV600E constituting a commonly encountered finding in a series of malignancies of different anatomical location, has led to further and important insights into the possibility to target molecular pathways apart from the origin of the respective malignancy. This development has resulted in the approval of nearly 70 new molecularly targeted drugs for cancer by the European Medicines Agency from 2007 to the present.This development and the very impressive translation of the identification of relevant molecular changes associated with cancer development and progression into clinical applicability by the use of targeted drugs have prompted us to launch a special issue of ESMO Open on upcoming, clinically relevant molecular targets in cancer. The papers addressing this topic will be published in ESMO Open in a special issue during the upcoming weeks and months and will widen the spectrum of such ‘special issues’, which have been devoted to upcoming targets of immunotherapy,1 side effects of immunotherapy2 and the ‘How I Treat Cancer’ series.3