In this review, we focus on studies of the viable but nonculturable response (VBNC) of Vibrio vulnificus, a significant and aggressive human pathogen, as a model system for the general understanding of the VBNC response. This response is characterized physiologically as the inability to culture an organism on media that normally supports its growth, and yet those cells retain indicators of metabolic activity. Implicit in this definition is that it may be possible to return or resuscitate VBNC cells to active division on laboratory media. Since its original description in 1985, the VBNC response has been recognized in a range of bacteria. Study of the VBNC response has traditionally focused on physiological methods aimed at demonstrating that VBNC cells are indeed viable but have a specific block that prevents them from dividing on laboratory media, and such study has attempted to identify conditions that unequivocally demonstrate the resuscitation of VBNC cells. With the advent of molecular genetics, VBNC studies have begun to focus on genetics as a means to determine whether there are specific genes or regulatory pathways responsible for the development of the VBNC response. Thus, by combining information from physiological and genetic experiments, it is hoped that it can be determined whether the VBNC response represents a genetically programmed physiological adaptation similar to sporulation and outgrowth or whether VBNC represents the slow loss of function on the way to cellular death.