The ancient phylum Apicomplexa includes many of the world’s pre-eminent protozoan pathogens. Most deadly to humans is Plasmodium, the agent of malaria, which kills around a million people annually. As obligate intracellular parasites, they establish intimate interactions with their hosts. Toxoplasma gondii is an extreme example of this adaptation, able to replicate within nearly every cell type in any warm-blooded host. Not only the developmental program of this parasite in wildlife and livestock animals can result in potentially negative socio-economic impact, but remarkably, in about a third of the human population Toxoplasma also experiences prolonged quasi-silent persistence in tissues such as brain and retina. While the asymptomatic parasitism that proceeds typically offers life-long equilibrium and protection in immune competent hosts, sustained immune dysfunction is known to break parasite dormancy, promoting bradyzoite to tachyzoite transition and further T. gondii tachyzoite population expansion, these combined processes eventually resulting in encephalitis and meningitis as major damages. The strategy of T. gondii as a parasite is based on a quest for avirulence, a capacity to attenuate but not to fully counteract the immune defense of the host, thus securing the permanent residence required to await transmission. HostQuest focuses on elucidating the molecular mechanisms by which T. gondii is orchestrating immune evasion and lifelong persistence in hosts. Once intracellular, parasites actively reprogram gene expression of the immune cells they infect by subverting host transcription factors activity or by modulating the epigenetic status of target genes. Secreted effectors are involved. Those are singularly exported beyond the vacuole-containing parasites and reach the host cell nucleus to reshape the host genetic program. The discovery of new exported Toxoplasma effectors and the characterization of their activities, or the mechanisms by which they are recognized by the host immune system, continues to gather pace. Much has been learnt in recent years but we have only been chipping at the tip of the iceberg. We aim to study the modus operandi of these effectors and particularly their possible implications in immune evasion and parasite persistence. These effectors may adopt at least three alternative, although not mutually exclusive, strategies to subvert host gene expression. They may (i) modulate upstream signaling pathways (ii) directly target host transcription factor protein levels/activity and/or (iii) affect histone packing and chromatin configuration. HostQuest is an interdisciplinary project that aims to: i) Determine the full repertoire of GRA effectors and the magnitude of the changes they are eliciting in the infected cell; ii) Explore their synergistic and/or antagonist effects on gene regulation; iii) Decipher the extent to which they contribute to immune evasion and/or sustained parasitism; iv) Gain knowledge of the three-dimensional structure of effectors in complex with host cell factors in order to understand the protein function or to guide further experiments to investigate function. Studies of effectors also continue to offer opportunities for the development of tools to probe host cell biology in the absence of disease. In this respect, HostQuest is also poised to exploit Toxoplasma molecular intelligence developed over million years of co-evolution with its hosts to learn new lessons on the mechanisms regulating cell homeostasis and their alterations in host cells, including cancer cells.