In October 2007, the Food and Drug Administration mandated significant revisions to product labeling for the commercially available echocardiographic contrast agents (ECA) Definity and Optison after spontaneous healthcare provider reports of 4 patient deaths and ≈190 severe cardiopulmonary reactions occurring in close temporal relationship to ECA administration. Since then, multiple large ECA safety studies have been published and have included outpatients, hospitalized patients (including the critically ill), patients undergoing stress echocardiography, and patients with pulmonary hypertension. In addition, the Food and Drug Administration has convened 2 Advisory Committee meetings and the product labels for Optison and Definity have been substantially revised with a softening of safety restrictions. In this review, we will address the safety of ECA use in patients with serious cardiopulmonary conditions, patients with intracardiac shunts, and special patient populations including pulmonary hypertension, pediatrics, and pregnancy. In addition, we will discuss the confounding role of pseudocomplication in attribution of adverse events during diagnostic testing, the current status of the ECA Black Box Warning, and recommended safety precautions during ECA administration.