Natural selection during the first Haplosporidium nelsoni-caused epizootic in Delaware Bay oysters resulted in the development of a degree of resistance to mortality caused by the pathogen throughout the Bay. Until the late 1980s, this level of resistance did not change because most of the surviving oysters were protected from additional selection as they resided in the low salinity region of the Bay. The development of a second level of resistance was signaled after heavy H. nelsoni-caused mortalities in the mid 1980s occurred during a severe drought and prevalence of the pathogen subsequently decline markedly. Susceptible controls exposed beside natural set in the lower bay continued to become heavily infected, whereas the natural set had prevalences of 0 to 10%. To determine whether oysters on the low-salinity beds were similarly resistant, we exposed oysters from two upper-bay beds along with lower bay natives and susceptible controls in Cape May Harbor where H. nelsoni pressure has been heavy. Six months later, prevalence of susceptible oysters was 90%, with most infections being advanced. At the same time, prevalence in the two upper bay groups was only 5 to 20 % with mostly light, localized infections. This confirms that a high degree of resistance is now present throughout the Bay. In contrast, there is little evidence that significant resistance to infection by Perkinsus marinus has developed despite continuous exposure and consequent mortality over the past 15 years.