Correlation studies between cytokines expressed in islets and autoimmune diabetes development in NOD mice and BB rats have demonstrated that β‐cell destructive insulitis is associated with increased expression of proinflammatory cytokines (IL‐1, TNFα, and IFNα) and type 1 cytokines (IFNγ, TNFβ, IL‐2 and IL‐12), whereas non‐destructive (benign) insulitis is associated with increased expression of type 2 cytokines (IL‐4 and IL‐10) and the type 3 cytokine (TGFβ). Cytokines (IL‐1, TNFα, TNFβ and IFNγ) may be directly cytotoxic to β‐cells by inducing nitric oxide and oxygen free radicals in the β‐cells. In addition, cytokines may sensitize β‐cells to T‐cell‐mediated cytotoxicity in vivo by upregulating MHC class I expression on the β‐cells (an action of IFNγ), and inducing Fas (CD95) expression on β‐cells (actions of IL‐1, and possibly TNFα and IFNγ). Transgenic expression of cytokines in β‐cells of non‐diabetes‐prone mice and NOD mice has suggested pathogenic roles for IFNα, IFNγ, IL‐2 and IL‐10 in insulin‐dependent diabetes mellitus (IDDM) development, and protective roles for IL‐4, IL‐6 and TNFα. Systemic administrations of a wide variety of cytokines can prevent IDDM development in NOD mice and/or BB rats; however, a given cytokine may retard or accelerate IDDM development, depending on the dose and frequency of administration, and the age and the diabetes‐prone animal model studied (NOD mouse or BB rat). Islet‐reactive CD4⁺ T‐cell lines and clones that adoptively transfer IDDM into young NOD mice have a Th1 phenotype (IFNγ‐producing), but other islet‐specific Th1 clones that produce TGFβ can adoptively transfer protection against IDDM in NOD mice. NOD mice with targeted deletions of IL‐12 and IFNγ genes still develop IDDM, albeit delayed and slightly less often. In contrast, post‐natal deletions of IL‐12 and IFNγ, also IL‐1, TNFα, IL‐2, and IL‐6—by systemic administrations of neutralizing antibodies, soluble receptors and receptor antagonists, and receptor‐targeted cytotoxic drugs—significantly decrease IDDM incidence in NOD mice and/or BB rats. These cytokine deletion studies have provided the best evidence for pathologic roles for proinflammatory cytokines (IL‐1, TNFα, and IL‐6) and type 1 cytokines (IFNγ, IL‐2 and IL‐12) in IDDM development. © 1998 John Wiley & Sons, Ltd.