Caution should be taken in considering immunoelectrofocusing (IEF) as the best method for the diagnosis of alpha-1-antitrypsin (A1AT) deficiency, particularly in some population, including Sardinians, in which a M-like variant represents the most frequent pathological A1AT variant. Regarding the future, my opinion is that the algorithm generally suggested for reaching a proper diagnosis of this disease should be completely changed. The cut-off of the A1AT serum values should be reconsidered, not to avoid the diagnosis of a number of heterozygous subjects who may be affected by liver and/or lung disease. Given that the two A1AT alleles are co-dominant, and since A1AT is a phase acute protein, in all heterozygous PiMZ or PiM/M-Cagliari subjects carrying an inflammation, the M allele is induced to produce high quantities of A1AT, whose serum levels may reach normal values. In these cases, PCR serum levels should be evaluated and, when increased, the diagnosis of A1AT deficiency should not be excluded even in the presence of serum A1AT levels within the normal range. Gene sequencing should be included, on the basis of our experience, in all neonates and pediatric patients with liver or lung disease of unknown origin, including asthma, avoiding IEF. Finally, for a screening in the perinatal period, I suggest the accurate examination of the electrophoresis of serum proteins. With a similar new approach, I think that we will transform A1AT deficiency from a rare disease into a previously rarely diagnosed disease, changing completely the epidemiology of this complex and fascinating metabolic disease.