Considerable efforts concerning the molecular characterization and targeted treatment of cancer have significantly improved treatment options and prognosis of tumor patients. Nevertheless, in tumor entities without recurrent genetic alterations the application of molecular testing for potentially targetable lesions remains heterogeneous and, in most cases, the approval of targeted therapies is still restricted to defined tumor entities harboring corresponding predictive biomarkers.The broad genomic analysis of different tumor entities including rare cancers within several genome sequencing initiatives and precision oncology programs has revealed the occurrence of addressable molecular alterations across many tumor entities, although their incidence may differ significantly in the context of the underlying cancer type. The treatment of molecularly defined patient cohorts demonstrated an impressive tumor-agnostic efficacy of certain therapeutics such as NTRK inhibitors, while the outcome of other targeted therapies, such as ERBB or BRAF inhibitors, varied in the context of the underlying disease.In the meantime, a handful targeted therapeutics addressing NRTK and RET fusions, the BRAF V600E mutation or different features of defective DNA mismatch repair and high tumor mutational burden has been approved for histology-agnostic treatment of tumors harboring these target lesions. Ongoing molecularly stratified basket trials will further investigate the tumor-agnostic efficacy of different targeted treatment approaches.