_Contents_: Introductory. Earliest period. _Francis Glisson_ as founder of the doctrine of irritability. _Albrecht von Haller._ The vitalists. _Bordeu_ and _Barthez_. _John Brown’s_ system. _Johannes Müller_ and the specific energy of living substance. _Rudolf Virchow’s_ doctrine of the irritability of the cell. Discovery of the inhibitory effects of stimulation. _Weber_, _Schiff_, _Goltz_, _Setschenow_, _Sherrington_. _Claude Bernard_ studies on narcosis. Tropisms. _Ehrenberg_, _Engelmann_, _Pfeffer_, _Strassburger_, _Stahl_. _Semon’s_ speculations on mneme. Irritability is a _general_ property of living substance but not exclusively so. Irritable systems also exist in inanimate nature. What characterizes living substances is not irritability as _such_, but an irritability of a specific type. The irritability of the living system can, therefore, not be studied alone, but as the properties of a living system are dependent upon each other, so this property must be considered with the others possessed by a living substance. In this sense irritability presents a problem of fundamental physiological importance. For if we could analyze the irritability of living substance to its essence, then the nature of life itself would be fathomed. The analysis of irritability of living substance offers us, therefore, a path to the investigation of life and herein lies the importance of the study of irritability. I wish to follow this path toward the knowledge of the vital processes and to endeavor to show in these lectures what information the analysis of irritability and that of the effect of stimuli can give us of the mechanism of the processes in living substance. Before doing so, however, I wish to consider somewhat more in detail the question as to how we have arrived at the conception of the nature of irritability. To the thinkers both in the field of physiology and medicine of ancient and mediæval times the conception of irritability was quite foreign. Even a comprehension of the nature of stimuli had not yet begun to crystallize from vague impressions of the various influences of different agents on the human being. Nevertheless they knew of such influences of the most varying kinds upon the human body. The ancients already possessed a materia medica, founded on the real or supposed influence of various mineral, vegetable and animal substances upon the organism. It was also known that heat and cold, light and darkness had an effect upon disease. They likewise believed in the influence of certain factors upon the health of man, which in reality have no effect whatsoever, as the stars and the magnet. But neither in ancient nor in mediæval times was the state of knowledge reached wherein generalizations were made from these agents, which had a real or supposed action upon the organism, and to combine these to a general conception of stimulation. The conception of stimulation and irritability cannot however be separated.