The diagnosis and management of food allergy is complicated by an abundance of homologous, cross-reactive proteins in edible foods and aeroallergens. This results in patients having allergic sensitization (positive tests) to many biologically related foods. However, many are sensitized to foods without exhibiting clinical reactivity. Although molecular diagnostics have improved our ability to identify clinically relevant cross-reactivity, the optimal approach to patients requires an understanding of the epidemiology of clinically relevant cross-reactivity, as well as the food-specific (degree of homology, protein stability, abundance) and patient-specific factors (immune response, augmentation factors) that determine clinical relevance. Examples of food families with high rates of cross-reactivity include mammalian milks, eggs, fish, and shellfish. Low rates are noted for grains (wheat, barley, rye), and rates of cross-reactivity are variable for most other foods. This review discusses clinically relevant cross-reactivity related to the aforementioned food groups as well as seeds, legumes (including peanut, soy, chickpea, lentil, and others), tree nuts, meats, fruits and vegetables (including the lipid transfer protein syndrome), and latex. The complicating factor of addressing co-allergy, for example, the risks of allergy to both peanut and tree nuts among atopic patients, is also discussed. Considerations for an approach to individual patient care are highlighted.