While worldwide prevention efforts for type 1 diabetes (T1D) are underway to abrogate or slow progression to diabetes, mass screening of islet autoantibodies (IAbs) in the general population is urgently needed. IAbs, the most reliable biomarkers, play an essential role in prediction and clinical diagnosis of T1D. Through laboratory proficiency programs and harmonization efforts, a radio-binding assay (RBA) has been well established as the current 'gold' standard assay for all four IAbs. However, in view of the need for large-scale screening in the non-diabetic population, RBA consistently faces two fundamental challenges, cost-efficiency and disease specificity. While all four IAbs are important for disease prediction, the RBA platform, with a separate IAb test format is laborious, inefficient and expensive. Furthermore, the majority of IAb positivity in screening, especially from individuals with single IAb were found to be low risk with low affinity. It is well documented from multiple clinical studies that IAbs with low affinity are low risk with less or no disease relevance. At present, two non-radioactive multiplex assays, a 3-assay ELISA combining three IAbs and a multiplex ECL assay combining all four IAbs, have been successfully used as the primary methods for general population screenings in Germany and the US, respectively. Recently, the TrialNet Pathway to Prevention study has been organizing an IAb workshop which aims to analyze the 5-year T1D predictive values of IAbs. A T1D-specific assay with high efficiency, low cost and requiring low volume of sample will definitely be necessary to benefit general population screening.