Human Cytomegalovirus (HCMV) is a leading cause of congenital infection and is associated with significant mortality in immunocompromised individuals. Currently available therapies suffer from significant side effects and/or the potential for drug resistance. A comprehensive understanding of the function of viral proteins is therefore critical for rationally-designed new treatments. We have previously shown that HCMV can regulate the abundance of thousands of host proteins and transcripts, leading to degradation of antiviral restriction factors, components of cell death pathways and proteins involved in viral sensing. HCMV also upregulates pro-survival proteins and proteins required for viral transcription and translation. However, a systematic understanding of which viral proteins drive each of these host protein-level changes is lacking. We have developed a large-scale proteomic screen to discover the whole HCMV ‘effectome’ for 170 canonical HCMV proteins and 17 novel ORFs. We used 18-plex tandem mass tags and RNAseq to multiplex lysates from 187 individual human fibroblast cell lines each stably expressing a single HCMV ORF, measuring ~8,000 human proteins and ~40,000 transcripts in each cell line. In addition to validating the up- or down-regulation of multiple positive controls, we characterised novel functions for multiple viral ORFs. This included a new role for previously uncharacterised ORFS343C in inhibition of MAPK signalling. In addition to presenting findings from this large screen, we will introduce insights into the overlap between this data and our previous proteomic analyses of HCMV, leading to a unified model of HCMV protein function.