In this essay, changes in the human hippocampal volume and function induced by stress, depression and physical exercise are examined. Hippocampus is crucially involved in the acquisition and retrieval of episodic and spatial memory, and hippocampal volume correlates with episodic and spatial memory performance. Hippocampus has substantial plasticity and changes with age, but also in response to experiential factors across life. Stress and, under at least some circumstances, also depression have negative effects on hippocampal volume and memory function. The negative effects are believed to accelerate age-related decline in volume and function, mediated by exaggerated cortisol levels and dysfunction in the HPA-axis. Physical exercise is examined from two perspectives; aerobic and strength exercise. Aerobic exercise increases hippocampal volume across various ages and decelerates age-related hippocampal degeneration, whereas support for strength exercise-induced effects are mixed and need to be studied further. The positive effects are believed to be mediated by increased BDNF levels and regional cerebral blood volume. Although hippocampal volume normally correlates with hippocampus-dependent memory, studies on exercise-induced changes in human hippocampus-dependent memory have reported inconsistent results. Animal studies have observed both the negative and positive effects on hippocampal volume to relate to changes in neurogenesis, cell proliferation, and dendritic complexity. The negative and positive effects on hippocampal volume have been observed to be non-permanent, suggesting that physical exercise may prevent, attenuate and possibly reverse hippocampal degeneration induced by stress and depression. Further, more studies on sex and age differences, exercise intervention designs and functional values of physical exercise would be of value.