Weaning is a critical event in the pig's life cycle, frequently associated with severe enteric infections and overuse of antibiotics; this raises serious economic and public health concerns. In this review, we explain why gut microbiota dysbiosis, induced by abrupt changes in the diet and environment of piglets, emerges as a leading cause of post-weaning diarrhea, even if the exact underlying mechanisms remain unclear. Then, we focus on nonantimicrobial alternatives, such as zinc oxide, essential oils, and prebiotics or probiotics, which are currently evaluated to restore intestinal balance and allow a better management of the crucial weaning transition. Finally, we discuss how in vitro models of the piglet gut could be advantageously used as a complement to ex vivo and in vivo studies for the development and testing of new feed additives.