Infectious gastroenteritis is a common illness afflicting people worldwide. The two most common etiological agents of viral gastroenteritis, rotavirus and norovirus are known to recognize histo-blood group antigens (HBGAs) as attachment receptors. ABO, Lewis, and secretor HBGAs are distributed abundantly on mucosal epithelia, red blood cell membranes, and also secreted in biological fluids, such as saliva, intestinal content, milk, and blood. HBGAs are fucosylated glycans that have been implicated in the attachment of some enteric pathogens such as bacteria, parasites, and viruses. Single nucleotide polymorphisms in the genes encoding ABO (H), fucosyltransferase gene FUT2 (Secretor/Se), FUT3 (Lewis/Le) have been associated with changes in enzyme expression and HBGAs production.The highly polymorphic HBGAs among different populations and races influence genotype-specific susceptibility or resistance to enteric pathogens and its epidemiology, and vaccination seroconversion. Therefore, there is an urgent need to conduct population-based investigations to understand predisposition to enteric infections and gastrointestinal diseases. This review focuses on the relationship between HBGAs and predisposition to common human gastrointestinal illnesses caused by viral, bacterial, and parasitic agents.