Herpes simplex virus (HSV)-1 and HSV-2 are ubiquitous human pathogens that infect keratinized epithelial surfaces and establish lifelong latent infection in sensory neurons of the peripheral nervous system. HSV-1 causes oral cold sores, and HSV-2 causes genital lesions characterized by recurrence at the site of the initial infection. In multicellular organisms, cell death plays a pivotal role in host defense by eliminating pathogen-infected cells. Apoptosis and necrosis are readily distinguished types of cell death. Apoptosis, the main form of programmed cell death, depends on the activity of certain caspases, a family of cysteine proteases. Necroptosis, a regulated form of necrosis that is unleashed when caspase activity is compromised, requires the activation of receptor-interacting protein (RIP) kinase 3 (RIPK3) through its interaction with other RIP homotypic interaction motif (RHIM)-containing proteins such as RIPK1. To ensure lifelong infection in the host, HSV carries out sophisticated molecular strategies to evade host cell death responses during viral infection. HSV-1 is a well-characterized pathogen that encodes potent viral inhibitors that modulate both caspase activation in the apoptosis pathway and RIPK3 activation in the necroptosis pathway in a dramatic, species-specific fashion. The viral UL39-encoded viral protein ICP6, the large subunit of the virus-encoded ribonucleotide reductase, functions as a suppressor of both caspase-8 and RHIM-dependent RIPK3 activities in the natural human host. In contrast, ICP6 RHIM-mediated recruitment of RIPK3 in the nonnatural mouse host drives the direct activation of necroptosis. This chapter provides an overview of the current state of the knowledge on molecular interactions between HSV-1 viral proteins and host cell death pathways and highlights how HSV-1 manipulates cell death signals for the benefit of viral propagation.