Allergen-specific immunotherapy (AIT) focuses on the IgE-mediated immune response to a single allergen(s). As a result, a monosensitized patient would be an excellent candidate for AIT. However, because the majority of patients are polysensitized, two major issues arise: first, if AIT with a clinically relevant allergen is helpful in polysensitized patients, and second, whether a few allergens or mixes (European approach) an including all potentially sensitizing allergens (USA approach) should be utilized. It is worth noting that the so-called “component resolved diagnosis” has just recently provided new diagnostic prospects. The existing experimental data on the contentious issues of single allergen vs multi allergen AIT are examined in this article. Some data are only accessible from isolated research, which are frequently inadequately controlled, and there have been few trials on the argument in recent years. According to big experiments using grass extracts, AIT can be useful in both monosensitized and polysensitized individuals. The evidence for the efficacy of allergen mixtures is currently limited, but component-resolved diagnostics might be a useful tool in allergen selection. Indeed, comparative trials on multiple allergen immunotherapy versus single allergen immunotherapy would be costly and time-consuming, which explains why there is a scarcity of data.