In this thesis, we have described the development of the infant gut microbiome and resistome, identified important environmental and nutritional drivers of this development, and studied the gut microbiome and cross-niche microbial network development in relation to health and disease. We have shown that mode of delivery impacts the gut microbiome composition, with infants born by caesarean section born infants carrying a higher abundance of potential pathogens such as Klebsiella and Enterococcus species in their gut. Interestingly, we could associate an increased abundance of these gut bacteria at one week of life with a higher susceptibility to respiratory tract infections in the first year of life. Next, we established that even a short course of early-life broad-spectrum antibiotics has long-term effects on the developing infant gut microbiome, selecting for potential pathogenic bacteria and leading to a higher abundance of antimicrobial resistance genes. In case of early-onset neonatal sepsis, we strongly advise treatment with the antibiotic combination of penicillin + gentamicin, as this affects the microbial and antibiotic resistance gene composition of the infant gut the least, when compared to co-amoxiclav + gentamicin or amoxicillin + cefotaxime. Additionally, we demonstrated that rectal swabs are a reliable proxy for fecal samples in infant gut microbiota research. Finally, using the fecal, saliva and nasopharyngeal samples collected, we could build cross-niche microbial networks and could associate fragmented networks with a higher susceptibility to respiratory tract infections. Altogether, the results of this thesis provide insights into multiple environmental factors driving the infant gut microbiome and resistome development and how these relate to health later in life.