Coadaptation between mistletoes and birds captured the attention of Charles Darwin over 150 years ago, stimulating considerable scientific research. Here we used Loranthaceae, a speciose and ecologically important mistletoe family, to obtain new insights into the interrelationships among its hosts and dispersers. Phylogenetic analyses of Loranthaceae were based on a dataset of nuclear and chloroplast DNA sequences. Divergence time estimation, ancestral area reconstruction, and diversification rate analyses were employed to examine historical biogeography. The crown group of Loranthaceae was estimated to originate in Australasian Gondwana during the Paleocene to early Eocene (59 Ma, 95% HPD: 53–66 Ma), and rapidly diversified, converting from root parasitic to aerial parasitic trophic mode ca. 50 Ma during the Eocene climatic optimum. Subsequently, Loranthaceae were inferred to be widespread in Australasia and South America but absent in Africa. The African and European members were derived from Asiatic lineages. The burst of diversification of Loranthaceae occurred during a climatic optimum period that coincides with the dominance of tropical forests in the world. This also corresponds to the trophic mode conversion of Loranthaceae and rapid radiation of many bird families – important agents for long-distance dispersal in the Cenozoic.