The rapid advances in the understanding of oncogenic process and the maturation of affordable precision diagnostic tools have enabled the development of targeted therapeutic agents, such as those targeting BCR-ABL, epithelial growth factor receptor L858R, EML4-anaplastic lymphoma kinase, and BRAF V600E, to treat cancers that harbor specific molecular alterations. Traditionally, each targeted drug has been developed for a particular tumor type where such alteration is most frequently found. Recently, the widespread adoption of next generation sequencing has led to an increase in the identification of rare and ultra-rare alterations, and, in some cases, the same rare alterations are found across multiple tumor types. The rarity of these alterations makes clinical trials traditionally designed for specific tumor types infeasible. As a result, tissue-agnostic trials have been developed to study the efficacy of these treatments and increase patient access. This review summarizes current successful cases of tissue-agnostic development, such as drugs targeting tropomyosin receptor kinase fusions, and proposes the next wave of potential tissue-agnostic targets, including fusions of ROS1, anaplastic lymphoma kinase, fibroblast growth factor receptor, and rearranged during transfection. In addition, the advantages and the challenges of such approach are discussed in the context of clinical development and approval.