The Mediterranean basin constitutes one of the largest global biodiversity hotspots, hosting more than 11,000 endemic plants, and it is recognised as an area with a high proportion of threatened taxa. Nevertheless, only a tiny fraction of the threatened Mediterranean endemics have their genetic diversity assessed, and we are unaware if and how climate change might impact their conservation status. This is even more pronounced in Eastern Mediterranean countries with a rich endemic flora, such as Greece, which hosts a large portion of the plant taxa assessed at the European level under the IUCN criteria. Using inter simple sequence repeats (ISSR) markers and species distribution models, we analysed the genetic diversity and investigated the impacts of climate change on four critically endangered and extremely narrow and rare Greek island endemic plants, namely Aethionema retsina, Allium iatrouinum, Convolvulus argyrothamnos, and Saponaria jagelii. All four species are facing intense anthropogenic threats and display moderate genetic diversity (uHe: 0.254–0.322), while climate change is expected to have a profound impact on their range size during the coming decades. A combination of in- and ex-situ measures, such as population reinforcement and seed bank conservation, are urgently needed in order to preserve these highly threatened and rare Greek endemics.