The management of cancer traditionally depends on the site of tumour origin and by specific histologic subtypes. However, with the introduction of molecular analysis to look for genetic aberrations, more novel genomically-driven treatment options have become possible. v-Raf murine sarcoma viral oncogene homolog B (BRAF) is one of the downstream signals in Mitogen-activated protein kinases (MAPK) pathway . BRAF and Mitogen-activated protein kinase (MEK) inhibitors, although approved for melanoma, non-small cell lung cancer (NSCLC) and colon cancer currently [2,3,4,5], have reported activity across other various cancers harbouring BRAFV600E (substitution of glutamic acid (E) for valine (V) at codon 600 of the BRAF protein) aberrations. The frequency of BRAF mutation of 22%, 2%, 12% and 90% has been reported among cholangiocarcinoma, pancreatic cancer, endometrial cancer and craniopharyngioma respectively in literature [6, 7,8,9]. We describe five cases of off-label use of double BRAF/MEK blockade in such tumours (Case.1 Cholangiocarcinoma; Case.2 Cholangiocarcinoma; Case.3 Pancreatic cancer; Case.4 Endometrial adenocarcinoma; Case.5 Craniopharyngioma) managed at the Sarah Cannon Research Institute, London leading to excellent clinical and radiological response and protracted duration of disease control, reiterating the fact that performing next-generation sequencing in all patients with cancers other than melanoma looking for targetable mutations such as BRAFV600E may be useful, as when found, can add on an effective and durable treatment option.