To illustrate the chronic nature and heterogeneity of islet autoimmunity and highlight critical gaps in knowledge, this figure depicts two hypothetical patterns of T cell–mediated β cell destruction and loss of insulin secretion: early triggering of insulitis and semi-linear β cell destruction (blue line); or late start of the autoimmune β cell destruction, closer to clinical diagnosis (red line). This is a simplified schematic representation: loss of β cell mass and insulin secretion may not always correlate and may vary based on the relative importance of autoimmune destruction and β cell dysfunction during disease progression in a given patient. Seroconversion for T1D-associated autoantibodies to native antigens is considered the earliest step in the triggering of islet autoimmunity; it occurs in early life in children at genetic risk of T1D, but it may occur later in life in many individuals. As only a minority of islets are affected at any given time, the process proceeds asynchronously. Residual β cell mass at onset may be a function of the severity of autoimmune destruction and initial mass, which are impacted by age. It is often incomplete at diagnosis, but it continues afterward, sometimes for years. Low levels of insulin secretion are detected in many patients even decades after diagnosis: some β cell regeneration occurs after diagnosis, and it has been hypothesized that regeneration may occur during the preclinical stage. Critical questions remain unanswered: To what extent and when does the detection of humoral and cellular responses in the circulation reflect insulitis and β cell destruction, and which responses are relevant? At what time are insulitis and β cell destruction triggered during the progression of islet autoimmunity? Is there a preferred order for autoantibody and T cell responses to native antigens and neoepitopes, and what are their relative roles in insulitis, β cell destruction, and disease onset (trigger/driver responses versus secondary responses)?