Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link between different PMDs,including Alzheimer disease(AD)and type 2 diabetes(T2D),AD and Parkinson disease(PD),and AD and prion disease.Among them,AD and T2D are the most preva-lent PMDs,affecting millions of people globally,while Aβ and hIAPP are the causative peptides respon-sible for AD and T2D,respectively.Increasing clinical and epidemiological evidences lead to a hypothesis that the cross-seeding of Aβ and hlAPP is more biologically responsible for a pathological link between AD and T2D.In this review,we particularly focus on(i)the most recent and important findings of amyloid cross-seeding between Aβ and hIAPP from in vitro,in vivo,and in silico studies,(ii)a mecha-nistic role of structural compatibility and sequence similarity of amyloid proteins(beyond Aβ and hIAPP)in amyloid cross-seeding,and(iii)several current challenges and future research directions in this less-studied field.Review of amyloid cross-seeding hopefully provides some mechanistic understanding of amyloidogenesis and inspires more efforts for the better design of next-generation drugs/strategies to treat different PMDs simultaneously.