The trabecular meshwork (TM) is known to be subjected to different types of stress such as mechanical, oxidative, and phagocytic stress. Although short-term exposure to these stresses is expected to elicit adaptive responses, long-term exposure may lead to permanent alterations in the tissue physiology and contribute to the pathologic increase in aqueous humor outflow resistance frequently associated with glaucoma. A fuller understanding of the cell-specific and tissue-specific responses to stress in the TM, including changes in gene and protein expression, signal transduction, and potential pathogenic effects, could lead to novel prevention and therapeutic strategies for glaucoma. This review summarizes the current information available about how the TM responds to mechanical, oxidative, and phagocytic stress, as well as the evidence supporting the role that such responses may have in the alterations of the TM in aging and glaucoma.