The relationship between depression and coronary heart disease is well-established, but causal mechanisms are poorly understood. The aim of this review is to stimulate different ways of viewing the relationship between depression and adverse outcomes following acute coronary syndrome (ACS) and coronary artery bypass graft (CABG) surgery patients. We present an argument for depression in ACS and CABG patients being a qualitatively distinct form from that observed in psychiatric populations. This is based on three features: (1) depression developing after cardiac events has been linked in many studies to poorer outcomes than recurrent depression; (2) somatic symptoms of depression following cardiac events are particularly cardiotoxic; (3) depression following an ACS does not respond well to antidepressant treatments. We propose that inflammation is a common causal process responsible in part both for the development of depressive symptoms and for adverse cardiac outcomes, and we draw parallels with inflammation-induced sickness behaviour. Clinical implications of our observations are discussed along with suggestions for further work to advance the field.