Human enteroviruses (HEVs) like the group B coxsackieviruses (CVBs) are prime candidates for infectious, environmental causes of human type 1 diabetes (T1D). Non-obese diabetic (NOD) female mice are well protected from T1D onset if inoculated with CVB when young. Older, prediabetic NOD mice can rapidly develop T1D following inoculation with CVB, mimicking clinical reports of disease-associated T1D onset. The ability to induce rapid T1D in NOD mice is linked to the rate of replication of the CVB strain in β cell cultures and pancreatic tissue, indicating that any CVB strain is potentially diabetogenic under the correct conditions. Rapid T1D onset is preceded by CVB replication in islet cells including β cells. Although CVB strains do not productively infect healthy islets of young mice, CVBs can replicate in healthy islets in the presence of murine IL-4. These models expand much of what is known or suspected regarding the etiologic role of HEVs in human T1D.