This article explains the principles of electrocardiography, and explains how it is used by Safety Pharmacology, with a focus on the requirement for multiple leads in Safety Pharmacology assessment. Electrocardiography as used in different disciplines (e.g., medicine, anesthesiology, physiology, and pharmacology/toxicology/safety pharmacology) has different requirements for the number of electrodes applied. Electrodes may be placed at an infinite number of points on the body, and voltages (electrocardiograms) may be registered between/among them. However in safety pharmacology there is little evidence that more than 1--or at most 3--lead(s) is (are) required to provide all of the information that might be present using an infinite number. This is based upon (1) the biophysics of the heart as a generator of electrical potential/voltage, (2) the fact that most properties of electrophysiology affected adversely by drugs are expressed as changes in durations, and (3) experience. A single, unipolar lead (V(3)) recorded from the left sternal border at the 5th intercostal space possesses minimal artifact and large, stable deflections. This lead allows for accurate measurement of heart rate and rhythm, durations of component deflections (e.g., PQ, QRS, QT), and J-point deviation. A greater number of leads seldom or never yield additional information that detects liabilities. Commonly voltages recorded between the right thoracic and left pelvic limbs (lead II) provides information similar to lead V(3), and lead II is easier to apply, and produces voltages with less artifact and similar to those in lead V(3). A lead measuring the voltage between the left and right thoracic limbs (lead I) along with lead II allows for estimating orientation of vectors in the frontal plane, but knowledge of these vectors seldom or never indicates liability of a test article.