Human Milk (HM) is the best source for newborn nutrition until at least six months; it exerts anti-inflammatory and anti-infective functions, promotes immune system formation and supports organ development. Breastfeeding could also protect from obesity, diabetes and cardiovascular disease. Furthermore, human colostrum (HC) presents a peculiar role in newborn support as a protective effect against allergic and chronic diseases, in addition to long-term metabolic benefits. In this review, we discuss the recent literature regarding “omics” technologies and growth factors (GF) in HC and the effects of pasteurization on its composition. Our aim was to provide new evidence in terms of transcriptomics, proteomics, metabolomics, and microbiomics, also in relation to maternal metabolic diseases and/or fetal anomalies and to underline the functions of GF. Since HC results are so precious, particularly for the vulnerable pre-terms category, we also discuss the importance of HM pasteurization to ensure donated HC even to neonates whose mothers are unable to provide. To the best of our knowledge, this is the first review analyzing in detail the molecular pattern, microbiota, bioactive factors, and dynamic profile of HC, finding clinical correlations of such mediators with their possible in vivo effects and with the consequent impact on neonatal outcomes.