Abstract Medullary thyroid cancer ( MTC ) is an aggressive malignancy responsible for up to 14% of all thyroid cancer‐related deaths. It is characterized by point mutations in the rearranged during transfection ( RET ) proto‐oncogene. The activated RET kinase is known to signal via extracellular signal regulated kinase ( ERK ) and phosphoinositide 3‐kinase ( PI 3K), leading to enhanced proliferation and resistance to apoptosis. In the present work, we have investigated the effect of two serine/threonine‐protein kinase B‐Raf (BRAF) inhibitors ( RAF 265 and SB 590885), and a PI 3K inhibitor ( ZSTK 474), on RET ‐mediated signalling and proliferation in a MTC cell line ( TT cells) harbouring the RETC 634W activating mutation. The effects of the inhibitors on VEGFR 2, PI 3K/Akt and mitogen‐activated protein kinases signalling pathways, cell cycle, apoptosis and calcitonin production were also investigated. Only the RAF 265+ ZSTK 474 combination synergistically reduced the viability of treated cells. We observed a strong decrease in phosphorylated VEGFR 2 for RAF 265+ ZSTK 474 and a signal reduction in activated Akt for ZSTK 474. The activated ERK signal also decreased after RAF 265 and RAF 265+ ZSTK 474 treatments. Alone and in combination with ZSTK 474, RAF 265 induced a sustained increase in necrosis. Only RAF 265, alone and combined with ZSTK 474, prompted a significant drop in calcitonin production. Combination therapy using RAF 265 and ZSTK 47 proved effective in MTC , demonstrating a cytotoxic effect. As the two inhibitors have been successfully tested individually in clinical trials on other human cancers, our preclinical data support the feasibility of their combined use in aggressive MTC .