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This paper traces the development of in-series cardiac assist devices and describes the contributions of engineering methodology to the analyis of the interaction between the device and the cardiovascular system. Special emphasis is placed on issues regarding the control and optimization of this method of assistance. Recent results of our theoretical and experimental investigations are summarized. These results demonstrate that automatic control of in-series cardiac assist devices is essential to their effectiveness and is critical for preventing untoward hemodynamic effects. Guidelines concerning the design of algorithms for optimization of cardiac assistance are discussed.