Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that represents a significant global health burden. In immunocompetent individuals, HCMV establishes a lifelong persistent and typically asymptomatic infection that is controlled by a multifaceted host immune response. However, immunocompromised patients, including transplant recipients and those with acquired immunodeficiency syndrome, are at a high risk of HCMV-associated morbidity and mortality. HCMV is also the most prevalent infectious cause of congenital disease, with the ability to cause neurodevelopmental complications. Cell-intrinsic immune responses are the first line of defence against viruses, mediated by constitutively expressed host proteins and processes that respond directly to virus infection. As a result of virus-host coevolution, viruses often antagonise antiviral host proteins by driving their downregulation, mislocalisation or inactivation. A quantitative proteomic analysis of HCMV infection published by our group found that at least 133 proteins are likely targeted for degradation by HCMV during early infection. For the project presented in this thesis, seven of these candidate antiviral factors were screened for antiviral activity using a novel restriction assay system and plaque assays. Two proteins, mixed lineage kinase domain-like pseudokinase (MLKL) and DmX-like protein 1 (DMXL1), were then selected for further mechanistic and functional characterisation. MLKL is the terminal effector of a form of cell death called necroptosis. Many herpesviruses suppress necroptotic signalling to evade cell death. However, the mechanism of HCMV-mediated inhibition of necroptosis has so far remained elusive. HCMV protein pUL36 was found to be necessary and sufficient for the downregulation of MLKL and the inhibition of necroptosis. pUL36 has previously been shown to inhibit another mode of cell death, apoptosis, making it a multifunctional cell death inhibitor. DMXL1 interacts with the vacuolar-type H+-ATPase to regulate endosomal acidification, with implications for endosomal trafficking, autophagy, immune signalling and many other cellular processes. The viral gene responsible for downregulation of DMXL1 was identified as pUS33A, which may recruit the E3 ligase Kip1 ubiquitination-promoting complex (KPC) to target DMXL1 for proteasomal degradation. Therapeutics currently available for treating HCMV are associated with significant toxicity and drug resistance. Characterisation of the protein-protein interactions underlying the viral evasion of cell-intrinsic immune responses may permit the development of small molecule therapeutics that disrupt these interactions and facilitate endogenous inhibition of viral replication. As well as contributing to our understanding of how HCMV regulates cell death and endosomal acidification, this thesis also presents proteomic data that will enable the identification of additional antiviral host proteins and the characterisation of virus protein function.