In 1987, at the American College of Cardiology national meeting, a group of physicians from Europe and the United States agreed to use the term ‘arrhythmogenesis’ to refer to an aggravation or provocation of arrhythmias resulting from any cause and specifically to use the word ‘proarrhythmia’ when such arrhythmogenesis is from drug therapy. Proarrhythmia is thus, defined as the potential of cardiac and non-cardiac drugs to induce or exacerbate arrhythmias. It is a relatively common finding in the hospitalized and outpatient settings. It was recognized since the early 1980’s, but still was considered an extremely unusual event. In many instances, unfortunately the first manifestation of proarrhythmia is death. We have identified multiple conditions and non-cardiac medications that have been reported in association with this entity. Basic concepts of ion-channels of the heart are provided in this review, to help understanding the rational of the pathophysiology, which remains of paramount importance, as it gives insight to the diagnosis, that is mostly based on electrocardiographic findings. The careful detection of the presence of comordid diseases, makes it possible to prevent, recognize, avoid mistreatment and treat the condition. We present an overview of the cardiac cellular electrophysiology, mechanisms of cardiac arrhythmias and explain the substrates and targets of the pro-arrhythmic actions of non-cardiac drugs.