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Cardiogenic shock following acute myocardial infarction is associated with high mortality, substantially unchanged for the previous 20 years. Several approaches have been sought to achieve a therapeutic breakthrough, from myocardial revascularization strategies to the use of mechanical circulatory support. Many issues are, as yet, unresolved. Systemic inflammation seems to play a key role but is still lacking in effective therapies, and is potentially compounded by the death spiral of hypoperfusion and/or artificial devices. In this review, a multitarget approach to cardiogenic shock following acute myocardial infarction is proposed.