Allergens are proteins capable of raising in predisposed (atopic) individuals an IgE-dependent type I hypersensitivity reaction, supporting allergic symptoms such as anaphylactic shock, asthma and rhinitis. Panallergens are evolutionarily conserved, ubiquitous components of several complex sources of allergens, which usually act as minor allergens, i.e., they do not react with the majority of sera from patients allergic to a given allergen source. However, their presence has important clinical implications in establishing the phenomenon of food-pollen cross-reactivity, in the interpretation of diagnostic tests and in the preparation of immunotherapy extracts. A T-lymphocyte component is necessary to support the panallergen-specific humoral IgE antibody response. While several excellent reviews are available regarding allergen cross-reactivity from the IgE-perspective, data on crossallergenicity from the T-lymphocyte standpoint are quite limited. Indeed, this is a crucial issue in the comprehension of polysensitization, since it is the initial exposure to conserved panallergens that may subsequently drive the allergic immune response towards major allergenic components, which at first proved non-sensitizing to a given patient, through a mechanism of intermolecular epitope spreading. Here, we will discuss data showing that a functionally relevant T-cell response to molecularly defined, conserved regions of panallergens can support cross-allergenicity in allergic patients. This subject is relevant to the comprehension of the natural history and to the clinical management of the majority of allergic patients, who suffer from multiple allergies.