Birth causes complex changes in the individual physiology and organ systems and certainly poses a big immune challenge. The sudden encounter with an antigen full world, with the exposure to food antigens, and the colonization of the skin and mucosa with microbiota, require a tolerant immune system. Nevertheless, neonates must also be able to deal with pathogens, which makes their immune system unique. T lymphocytes are responsible for the coordination of the adaptive immune system response, the elimination of infected cells and the type of immune response and memory. It has been shown that neonatal cells have intrinsic differences with adult cells, biased towards an innate response and a tolerant phenotype. In the perinatal period, the immune system changes from basal signaling and innate like responses, towards stimulus-specific signals, which increase with gestational age. After birth the cells of the immune system continue to change both in composition and function. In this review, we present the intrinsic differences of neonatal CD4+ and CD8+ T cells, as compared with adult naïve cells. A specific transcriptome profile is present in both CD4+ and CD8+ neonatal T cells, with overexpression of homeobox transcription factors. These cells also present differences in cell signaling and metabolic characteristics, which result in unique functional capabilities. Neonatal CD4+ T cells respond differently from adult cells, with a high production of IL-8, a prevalent Th2 over Th1 profile, and an innate inflammatory response. The neonatal period is one of the most vulnerable periods of life, with a high morbidity and mortality rate, approaching on average 17 deaths per 1000 live births worldwide. A better understanding of the neonatal immune system will help to ensure a better care of this vulnerable population.