Chromosomal rearrangements or deletions can generate novel gene fusions that lead to the expression of chimeric proteins with oncogenic activity in lung and other cancers. The paradigm for gene fusions in lung cancer is the EML4-ALK gene fusion which is found in approximately 5% of lung adenocarcinomas.1 Once identified, drug development for this target proceeded rapidly and crizotinib was the first approved tyrosine kinase inhibitor for patients with ALK+ non-small cell lung cancer based on its ability to generate substation objective response rates and prolonged progression free survival (NSCLC).3,4 The development of CNS penetrant and/or next generation ROS1 inhibitors including lorlatinib, entrectinib and TPX-0005 is ongoing. RET gene fusions are also found in 1-2% of NSCLC, but the use of multiple different RET inhibitors have failed to reproduce the success of targeting ALK or ROS1 fusions.5 The development of more selective RET inhibitors such as LOXO-292, BLU-667, and RXDX-105 are currently in clinical trials for RET+ lung and other cancers. NTRK1 fusions were recently identified in NSCLC and homologous NTRK2 and NTRK3 fusions are found in multiple tumor types.6,7, Early clinical trials of larotrectinib showed an impressive objective response rate of 76% for 12 different tumor histologies harboring NTRK1/2/3 fusions and the CNS-penetrant entrectinib is similarly being evaluated in a basket trial. Other rare, novel fusions have recently been identified in NSCLC including EGFR fusions or MET fusions.7 Early evidence suggests that these fusions may also respond to cognate TKIs. EGFR fusions break the paradigm of ALK and ROS1 fusions in which the 5’ end of ALK or ROS1 is replaced with the 5’ portion of another gene. EGFR fusions retain most of the EGFR gene, with the unrelated gene sequencing fusing at the 3’ end of EGFR. A related oncogenic EGFR mutation in which the kinase domain of EGFR is duplicated in tandem has also been described and appears responsive to EGFR TKIs.7 Additional fusions involving the receptor tyrosine kinase (RTK) encoding genes AXL, PDGFRA, and ERBB4 fusions have been described, but little is known about the true incidence in lung cancer.8,9 The fusions described thus far all involve genes that encode RTKs, but additional gene fusions have also been identified in lung cancer including BRAF fusions.7,9 BRAF fusions replace the 5’ region of BRAF, including the Ras-binding domain (RBD), with sequences from another gene. Anecdotal evidence suggests that these alterations may be responsive to MEK inhibition. Analogous splice alteration which remove a region including the RBD have also been described in cancer and are oncogenic. Finally, gene fusions involving NRG1, which encodes the HER3/4 ligand neuregulin-1, have been described, mostly in invasive mucinous adenocarcinomas of the lung.9,10 Several challenges exist to the development of targeted therapies for these novel fusions. Even in the era of next-generation sequencing tests these alterations may go undetected due to limited testing of genes to those with approved therapies (ALK, ROS1, EGFR, and BRAF) and not all assays are designed to detect all of these alterations. Furthermore, the rarity of some of these alterations may make clinical trials for these novel fusions less appealing, although amalgamating some of these alterations with analogous mutations, e.g., MET gene fusions with MET exon 14 splice alterations or MET gene amplification, may allow for a more rapid path to approval.