In recent years, there has been remarkable progress in our understanding of cancer biology, host responses, and the concept of precision oncology. These advances have focused attention on biomarker-driven, tissue-agnostic drug development strategies. The recent approvals by the FDA of pembrolizumab for the treatment of unresectable or metastatic, microsatellite instability–high or deficient mismatch repair solid tumors, and more recently for the treatment of tumor mutational burden–high tumors; and of larotrectinib and entrectinib for the treatment of neurotrophic tyrosine kinase (NTRK) fusion–positive solid tumors, have further heightened interest in target-driven as opposed to histology-driven drug development. Herein, we focus on tissue-agnostic clinical drug development with an understanding of target modulation in the context of histology. The use of molecular genetics and biomarker-driven strategies rather than traditional histology based on organ of origin has reinforced the concept of tissue-agnostic drug development. Recent approvals in the United States, Europe, Japan, Australia, and other regions have further heightened interest in target-driven as opposed to histology-driven drug development.