Allergic rhino-conjunctivitis and asthma are induced by sensitization to one or more allergens in susceptible individuals. Specific immunotherapy (SIT) is indicated in allergic diseases, because it modulates the immune response inducing peripheral T-cell tolerance and activation of regulatory T-cells. On this basis, SIT is considered the only therapeutic approach that can modify the natural history of the allergic diseases. The development of engineered-allergen has contributed to reduce the allergenicity thus preventing the risk of side effects. The monomeric allergoids, with structural conformation and molecular size that facilitate the mucosal absorption, carry a lower risk for side effects compared to the administration of native allergens, maintaining the immunological stimulation. The efficacy of SIT, administered percutaneously (SCIT) or sublingual (SLIT), has been largely demonstrated in rhino-conjunctivitis; moreover, clinical trials have also demonstrated the efficacy of immunotherapy in allergic asthma. A therapeutic effect on asthma control has been shown in asthmatic subjects allergic to house dust mites, parietaria or grass pollen. An important and intriguing aspect of immunotherapy, not shared with the standard pharmacological treatments, is the long-lasting effect after discontinuation. In this respect, several SLIT studies in adults and children have clearly shown that the beneficial effects are maintained for up to 6 years after discontinuation of immunotherapy. The current review describes the main indications for SIT, and discusses its efficacy and safety in allergic rhino-conjunctivitis and asthma.