Pathogens deploy effector proteins to exploit host cell biology, yet most pathogen open reading frames (ORFs) are rapidly evolving and lack functional annotation. To address this, we developed the eORFeome, a scalable functional genomics platform encompassing 3,835 effector ORFs from diverse viruses, bacteria, and parasites. We screen for modulators of human signalling pathways and this PRIDE deposit contains the supporting mass spectrometry datasets, including AP‑MS, BioID, and whole‑cell MS for selected hits such as U14 (HHV6A) and Rave (Legionella).