Massive mortality outbreaks in cultured bivalves have been reported worldwide and they have been associated with infection by a range of viral and bacterial pathogens. Due to their economic and social impact, these episodes constitute a particularly sensitive issue in Pacific oyster (Crassostrea gigas) production. Since 2008, mortality outbreaks affecting C. gigas have increased in terms of intensity and geographic distribution. Epidemiologic surveys have lead to the incrimination of pathogens, specifically OsHV-1 and bacteria of the Vibrio genus, in particular Vibrio aestuarianus. Pathogen diversity may partially account for the variability in the outcome of infections. Host factors (age, reproductive status…) including their genetic background that has an impact on host susceptibility towards infection, also play a role herein. Finally, environmental factors have significant effects on the pathogens themselves, on the host and on the host-pathogen interaction. Further knowledge on pathogen diversity, classification, and spread, may contribute towards a better understanding of this issue and potential ways to mitigate the impact of these outbreaks.