This dissertation traces the cultural impact of introduced infectious disease in Hawai‘i from the arrival of Europeans to 1840. Colonialism in Hawai‘i began with challenges to Islander health, and I argue that health remained the national crisis of the Hawaiian Islands for over a century. More chronic than labor strife and land-use disputes, more pressing than self-determination and the struggle for sovereignty, the introduction of Old World diseases—bearing directly on the above challenges—resulted in drastically reduced lifespans, crushing infertility and infant mortality, and persistent poor health for generations of Hawaiians. The ma‘i malihini (introduced diseases) also left a deep imprint on Hawaiian culture and on the Hawaiian national consciousness. While scholars have noted the role of epidemics in the depopulation of Hawai‘i and broader Oceania, few have considered the effects of Old World diseases on Hawaiian culture—including religion, medicine and ideas about the body, and gender and sexuality. Equally neglected by scholars have been Islanders’ own ideas about—and responses to—disease and other health challenges on the local level. Scholars’ grasp of the Hawaiian past is therefore incomplete. My work aims to fill this important gap, while at the same time providing a comparative case study for disease and culture change among indigenous populations across the Americas and the Pacific.