Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known as human herpes virus 1 and 2 (HHV-1 and HHV-2), are two members of the herpes virus family, herpes viridae, which infect humans. Both HSV-1 (which produces most cold sores) and HSV-2 (which produces most genital herpes) are ubiquitous and contagious. They can be spread when an infected person is producing and shedding the virus. Herpes Simplex can be spread through contact with saliva, such as sharing drinks. HSV-2 is one of the most prevalent sexually transmitted infections worldwide. In addition to recurrent genital ulcers, HSV-2 causes neonatal herpes, and is associated with a 3-fold increased risk for HIV acquisition. Many HSV-2 vaccines have been studied in animal models, however, few have reached clinical trials, and those that have been tested in humans were not consistently effective. Here, I review HSV-2 pathogenesis, with a focus on novel understanding of mucosal immunobiology of HSV-2, and vaccine efforts to date, in an attempt to stimulate thinking about future directions for development of effective prophylactic and therapeutic HSV-2 vaccines.