A number of experimental and clinical evidence has shown that exposure to high amounts of allergen molecules favours the development of tolerance. This is true also for subcutaneous immunotherapy (SCIT), for which a dose dependence of clinical efficacy was clearly demonstrated. The effective doses, measured as μg of major allergens, to be administered during maintenance treatment were established for the main allergens. Regarding pollens, the range of effectiveness corresponds to 25-41 and 13-20 μg of major allergens Phl p 5 and Phl p 6 for grasses, to 10-47 μg of Amb a 1 for ragweed, to 12 μg of Bet v 1 for birch, and to 6.2 μg of Par j 1 for Parietaria. With house dust mites, a maintenance dose of 5-11.5 μg of the major allergen from Dermatophagoides pteronyssinus Der p 1 is associated to clinically relevant effects, and with cat epithelium the clinical success is observed using a dose of 13-15 μg of Fel d 1. Nevertheless, there are adverse reactions facing SCIT, which are related to the amount of injected allergen. In fact, the safety decreases when the administered doses increase. This has led to “optimal doses” being defined which show a good balance between efficacy and safety (corresponding for example to a dose of 7 μg for Der p 1 and of 13 μg for Fel d 1). The dose dependency with respect to both efficacy and safety makes essential to accurately consider the risk/benefit ratio in each patient eligible for SCIT.