Drugs that increase the contractile power of the myocardium and thus enhance its capability and efficacy are called cardiotonic agents. Cardiac insufficiency. can be defined as an inability of the heart to pump a sufficient amount of blood to supply oxygen and nutrients to organs and tissue, which leads to fatigue, shortness of breath, and edema. Cardiac insufficiency is most often caused by arterial hypertension and ischemic heart disease. Cardiotonic drugs are intended for treating cardiac insufficiency. This chapter focuses on cardiac glycosides isolated from leaves of various types of foxglove and strophanthus plant, and also a number of other plants such as lilies, periploca, oleander, hellebore, erysimum, jute, and Irish ballon. These drugs help in the strengthening of systole, which creates a more economic condition for heart work and strengthen myocardium contractions. Strong systolic contractions change into periods of diastole, which facilitate restoration of energetic resources of the myocardium. The chapter also discusses about other positive inotropic drugs such as Amrinone and Milrinone, highlighting their differences from glycosides, their chemical structure and their specific uses.