Symbiosis between corals and their dinoflagellate symbionts supports highly diverse coral reef ecosystems, which are increasingly threatened by anthropogenic climate change. The acquisition of novel, thermotolerant symbionts has been proposed as a natural or assisted mechanism of increasing reef resilience, but the cellular consequences of novel symbiotic associations are unclear. We used liquid chromatography-mass spectrometry to investigate the effects of a novel symbiosis on the host proteome of a model cnidarian. Aposymbiotic Exaiptasia were colonised by either the homologous symbiont (Symbiodinium minutum) or a thermally tolerant, ecologically invasive heterologous symbiont (Symbiodinium trenchii). Cnidarians hosting S. trenchii exhibited minimal expression of Niemann-Pick C2 proteins, which are important in sterol transport and cell recognition, and glutamine synthetases, which are essential for nitrogen recycling. Many proteins utilized by apicomplexans to parasitize mammals were differentially expressed between symbioses and between symbiotic states. The pathways in which these proteins function are likely important determinants of successful symbiosis establishment, and their identification may elucidate the features responsible for the physiologically suboptimal symbiosis with S. trenchii, despite its thermotolerance. The capacity of the two partners to integrate their metabolisms may limit the ability of corals to establish novel, thermally tolerant symbioses in response to climate change.