Tree nuts are clinically associated with severe immunoglobulin E-mediated systemic allergic reactions independent of pollen allergy and with reactions that are usually confined to the oral mucosa in patients with immunoglobulin E directed toward cross-reacting pollen allergens. The latter reactions can progress to severe and life-threatening episodes in some patients. Many patients with severe tree nut allergy are co-sensitized to peanut. Clinical studies on cross-reactivity between the tree nuts are few in number, but based on reports to date, avoidance of the other tree nuts once sensitivity is diagnosed appears prudent unless specific challenges are performed to ensure clinical tolerance. Even then, great care must be taken to avoid cross-contamination. As with other severe food allergies, a recurrent problem in clinical management is the failure of physicians to prescribe self-injectable epinephrine to patients who are at risk of anaphylaxis.