Empirical evidence that two genuine signatures are never identical in practice has been available for more than 120 years, but a scientific explanation for this phenomenon is lacking. The authors present a detailed explanation based on the latest research in biomedical sciences, identifying four reasons: 1) The “strokes” of each signature last 1/10 of a second, while the visual reaction time in humans requires at least 2 /10 of a second, so the “strokes” cannot be corrected by visual feedback. 2) Each time a signature is written, different motor units of the corresponding muscles are quasi-randomly activated, resulting in slightly different movements and thus a non-identical signature. 3) In writing a signature, muscles of the forearm and the rest of the upper limb are used, which are less controllable from the motor cortex than the intrinsic muscles of the hand. 4) It is implied by electromyogram studies and kinesiology that a unique sequence of muscle movements is required to produce a specific signature or handwriting, so if a person tries to repeat the same movement, the two actions will never be identical. In addition to the above, people usually sign “by heart” without seeing a model of their signature, using their “muscular memory”, thus producing non-identical signatures.