Development in the 1950s of the transseptal technique for left heart catheterization is described. Initial studies in animals and human cadavers were followed up by left atrial puncture with measurements of left atrial and left ventricular (LV) pressure (the latter using a small plastic catheter) in patients with cardiac disease. Many such procedures were performed safely without complications. Subsequent modification of the original technique for percutaneous catheter insertion allowed placement of a larger taper-tipped catheter in the LV chamber for selective LV angiography. Early clinical research studies at the National Heart Institute were performed using the transseptal method; these included investigation of the effects of increasing afterload on the normal and failing left ventricle by means of a graded angiotensin infusion to induce a progressive increase in aortic pressure. A marked decrease in the stroke volume occurred with increased afterload in the failing heart. This finding later led to the concept of afterload mismatch with limited pre-load reserve. Another early transseptal catheterization study in which measurements of LV pressure were made at different locations within the left ventricle as well as in the left atrium confirmed the presence of cavity obliteration in some patients and true obstruction in the LV outflow tract in many others. In addition, left ventriculography showed that obstruction was caused by abnormal anterior position during systole of the anterior mitral valve leaflet. With growing acceptance of retrograde catheterization of the left ventricle, the use of the transseptal technique for diagnostic purposes declined. However, in recent years, substantial renewed application of the transseptal method has occurred for special diagnostic and therapeutic purposes, including balloon valvuloplasties and electrophysiologic ablation procedures within the left heart.