Islands provide refuge for many rare and endemic species but are especially vulnerable to invasion by nonnative species. Invasive alien species are a major factor in the imperilment and extinction of island biota. Biosecurity protocols are designed to prevent or quickly detect the transport of harmful nonnative species, with the goal of eliminating the high economic cost of invasive species removal and the biological cost of damage caused by nonnative organisms. Effective biosecurity protocols require a balanced approach to on-island monitoring, off-island surveillance and prevention practices, rapid response, and educational outreach. Here we use the biosecurity program on Santa Cruz Island, California, to illustrate how risk evaluation, program priorities, and funding constraints intersect to define programmatic scope. Santa Cruz Island land managers have chosen to invest in early detection programs such as remote camera trapping, off-island prevention and education, and rapid-response planning for rats and in on-island biosecurity to prevent the spread of the most harmful plant species. We suggest that biosecurity efforts will be more effective—as well as cost effective—as an archipelago-wide initiative than as a single-island program. A newly formed collaboration with managers of other California Islands is designed to enhance visibility of the biosecurity initiative and attract new funding sources. With the economy afforded by collaboration, we will expand our program and prioritize annual audits, augment educational programs, measure project success, and increase compliance with and effectiveness of biosecurity protocols.