Devil facial tumour disease (DFTD) is a transmissible cancer devastating the Tasmanian devil (Sarcophilus harrisii) population. Since 1996, the survival of the Tasmanian devil has been threatened by DFTD, which now includes two genetically distinct transmissible cancers (DFT1 and DFT2). DFT1 is usually fatal and has resulted in an estimated total population decline of greater than 80%. The potential impact of DFT2 remains unknown, as the first case was documented in 2014.  The DFT1 and DFT2 cancer cells are the ‘infectious’ agents transmitted as an allograft by biting. Animals usually die within a few months with limited evidence of antibody or immune cell responses against the DFTD allograft. The lack of anti-tumour immunity with DFT1 is most likely due to an absence of cell surface MHC-I expression. Immune escape mechanisms and the cellular origin of DFT2 are still to be confirmed. Protection with a vaccine or treatment with immunotherapy offer strategies to prevent the dramatic decline in the devil population. The basis of the vaccine strategy is to treat DFT1 cells with IFN-γ to upregulate MHC, inactivation by irradiation or sonication and injecting them in association with the TLR agonists imiquimod and polyI:C. This strategy is producing humoral immune responses in almost all devils immunised, but it is not known if this will offer protection in the wild. For immunotherapy, live DFTD cells expressing MHC-I corresponded with anti-tumour responses in devils in some diseased devils. Tumour regression correlated with immune cell infiltration and DFT1 specific antibody responses. These data support the concept that immunisation of devils with modified DFTD cancer cells can induce humoral responses against DFT1 and trigger immune-mediated regression of established tumours. However, many questions remain including the cellular origin of DFT2 and why devils have been inflicted with two independent transmissible cancers.