Purpose of Review Galactose-alpha-1,3-galactose (alpha-gal) is a carbohydrate allergen with several unique characteristics. In this article, we discuss some recent advances in our understanding of the 'alpha-gal syndrome,' highlight data supporting the role of ticks in pathogenesis, and speculate on immune mechanisms that lead to sensitization. Recent Findings First described as the target of IgE in individuals suffering immediate hypersensitivity reactions to the novel anti-EGF monoclonal antibody cetuximab, it is now clear that a-gal sensitization is associated with mammalian meat allergy as well as reactions to other mammalian products. Unlike traditional IgE-mediated food allergies, reactions to a-gal often do not manifest until several hours following an exposure, although co-factors can influence the presentation. Multiple pieces of evidence, including recent work with a mouse model, point to the fact that sensitization is mediated by exposure to certain hard ticks and increasingly we are aware of its globally widespread impact. Summary The oligosaccharide a-gal represents a novel allergen with several unusual clinical features. It has been recognized now on multiple continents and its clinical presentation can be quite variable. Moreover, efforts to delineate the mechanisms leading to a-gal sensitization may have ramifications for our broader understanding of type 2 immunity.