It is now clear that antibiotic treatment in the antenatal period significantly does prolong pregnancy during conservative management of preterm premature rupture of membranes and reduces neonatal infectious diseases as well as neonatal-related morbidities. In the same way, prophylactic intrapartum antibiotherapy reduces the incidence of early-onset group B Streptococcus-induced sepsis. Nevertheless, on the other hand, antibiotics in the perinatal period are associated with an increase of neonatal sepsis by organisms resistant to maternally administered antibiotics. In addition, antibiotic treatment in this period of time is emerging as one of the possible sources of the dramatic increase in atopic disorders in infants and children owing to the interference with the normal process of intestinal microbial colonization. So, guidelines for using antibiotics in the perinatal period can be said as one of the major priority in public health. Antibiotics have therefore to be rightly choosen and must be used in a rational manner. Local microbial epidemiology, period of infection onset, clinical evaluation, all together allow the physician to use antibiotics, always in association, according to the "well-thought-out wager". In addition, the pharmacodynamic/pharmacokinetic relationship of each drug has to be known, in order to increase efficacy, decrease toxicity and reduce microbial resistance. It is especially mandatory in neonatology where the differences in drug distribution and drug elimination are of great concern, as compared to children and adults. The aim of this paper is to point out such very important aspects using antibiotics in the perinatal period.