Glutamine (GLN), which is the most abundant free amino acid of the human body, is an important cellular fuel and an essential precursor for the antioxidant glutathione (GSH). GLN plays a regulatory role in several cell specific processes, such as metabolism, protein synthesis and degradation, and respiratory burst. Severe GLN deficiencies usually occur rapidly in critical illness. GLN has regulatory capacity in immune and cell modulation, and GLN reduces morbidity and mortality in critical illness. The expression of heat shock proteins (HSP) is vital to cellular and tissue protection in stress or injury. GLN can function as a metabolic fuel and stress-signaling molecule in illness and injury via HSP. GLN has the ability to enhance HSP expression in injury, regulate the expression of some genes related to metabolism, signal transduction, cell defense and repair, and activate intracellular signaling pathways. The focus of this review is to describe how GLN participates in the regulation of illness and health and regulates the expression of HSP.