Type 1 diabetes (T1D) arises from a failure to maintain tolerance to specific β-cell antigens. Antigen-specific immunotherapy (ASIT) aims to reestablish immune tolerance through the supply of pertinent antigens to specific cell types or environments that are suitable for eliciting tolerogenic responses. However, antigen-presenting cells (APCs) in T1D patients and in animal models of T1D are affected by a number of alterations, some due to genetic polymorphism. Combination of these alterations, impacting the number, phenotype, and function of APC subsets, may account for both the underlying tolerance deficiency and for the limited efficacy of ASITs so far. In this comprehensive review, we examine different aspects of APC function that are pertinent to tolerance induction and summarize how they are altered in the context of T1D. We attempt to reconcile 25 years of studies on this topic, highlighting genetic, phenotypic, and functional features that are common or distinct between humans and animal models. Finally, we discuss the implications of these defects and the challenges they might pose for the use of ASITs to treat T1D. Better understanding of these APC alterations will help us design more efficient ways to induce tolerance.