Between 1957 and 1959, a previously unknown sporozoan parasite, now designated as Haplosporidium nelsoni (formerly Minchinia nelsoni), or MSX, killed 90–95% of the oysters in lower Delaware Bay. Native oysters have been studied for more than 20 years since then to determine long-term disease and mortality patterns resulting from this host-parasite association. Development of resistance to MSX-kill in native oysters has reduced disease mortality to about half the original level, even though the pathogen continues to be very active in the bay. Since the initial epizootic, MSX levels have fluctuated in a cyclic pattern with peaks every 6 to 8 years. Periods of low disease pressure follow very cold winters, while average or above average winter temperatures correlate with high MSX activity. During peak years, every oyster in the lower bay may become infected. Although the parasite is salinity limited, salinities in the lower bay, the area from which oysters are marketed, are nearly always favorable for MSX, and fluctuations in river flow have almost no effect on MSX in this region. Infection periods recur each summer. Some oysters die soon after becoming infected; others survive through winter, but die in spring as the pathogen compounds normal overwinter stresses. Many survivors are able to suppress or rid themselves of infections when temperatures approach 20°C in late spring. Resistance to MSX-kill in native oysters is not correlated with an ability to prevent infection, but with restriction of parasites to localized, nonlethal lesions. The persistence of “hot spots” for infection in areas where oysters are sparse, the lack of spores in infected oysters, and failure to transmit the disease experimentally lead to the hypothesis that an alternate or reservoir host produces infective stages of MSX.