Human cytomegalovirus (HCMV) is a major modulator of the immune system leading to long-term changes in T-lymphocytes, macrophages, and natural killer (NK) cells among others. Perhaps because of this immunomodulatory capacity, HCMV infection has been linked with a host of deleterious effects including accelerated immune aging (premature mortality, increased expression of immunosenescence-linked markers, telomere shortening, speeding-up of epigenetic “clocks”), decreased vaccine immunogenicity, and greater vulnerability to infectious diseases (e.g., tuberculosis) or infectious disease-associated pathology (e.g., HIV). Perhaps not surprisingly given the long co-evolution between HCMV and humans, the virus has also been associated with beneficial effects, such as increased vaccine responsiveness, heterologous protection against infections, and protection against relapse in the context of leukemia. Here, we provide an overview of this literature. Ultimately, we focus on one other deleterious effect of HCMV, namely the emerging literature suggesting that HCMV plays a pathophysiological role in psychiatric illness, particularly depression and schizophrenia. We discuss this literature through the lens of psychological stress and inflammation, two well-established risk factors for psychiatric illness that are also known to predispose to reactivation of HCMV.