Enterotoxigenic Escherichia coli (ETEC) are a major cause of traveler's diarrhea and infant mortality in developing countries. Given the rise of antibiotic resistance worldwide, there is an urgent need for the development of new preventive strategies. Among them, a promising approach is the use of probiotics. Although many studies, mostly performed under piglet digestive conditions, have shown the beneficial effects of probiotics on ETEC by interfering with their survival, virulence or adhesion to mucosa, underlying mechanisms remain unclear. This review describes ETEC pathogenesis, its modulation by human gastrointestinal cues as well as novel preventive strategies with a particular emphasis on probiotics. The potential of in vitro models simulating human digestion in elucidating probiotic mode of action will be discussed.