It is a striking principle of biology that the activity of living substance tends to inhibit its further activity. Carried to a moderate degree, this inhibition leads to the self-preservation of the living substance—to an extreme degree, to its self-destruction. The characteristics of this inhibition, its accompanying phenomena within the organism and the causes that lead to it form the subject of the present lecture. Fatigue is a comprehensive term, comprising, in its simple form, the functional state of the organism and its constituent parts after activity. Lying on the border zone where the physiologic and the pathologic meet, it reaches far into both and obscures the division lines between them. When present in slight or moderate degree, it limits achievement, but is easily recovered from; when excessive or an accompaniment of disease, it forms a serious condition, which, if in man, the medical practitioner must meet and combat.