Peanut and tree nut allergies have become a public health problem over the last 2 decades. The diagnostic procedure relies on a suggestive history, as well as on evidence of sensitization (skin prick testing and/or specific IgE blood testing), followed in selected cases by a food challenge. Standard IgE tests may be positive to more than 1 nut, due to cross-reactivity (allergens common to several nuts) or cosensitivity (frequently associated positive test results without cross-reactivity). Thus, many patients with a peanut or a tree nut allergy avoid all nuts, relying on positive test results without clinical evidence of reactivity. In addition, coexisting pollen sensitivity may add to diagnostic uncertainty due to potential cross-reactivity between pollens and nuts. In this article, we discuss challenges in diagnosis and clinical management of peanut and tree nut allergy related to cross-reactivity and cosensitization, as well as the avoidance of nuts tested positive to reduce the risk of reactions by cross-contamination. Studies to provide more accurate characterization of genuine clinically relevant cross-reactivity or cosensitivity to multiple nuts are needed.