The mitochondrion plays a crucial role in the immune system particularly in regulating the responses of monocytes and macrophages to tissue injury, pathogens, and inflammation. In systemic diseases such as atherosclerosis and chronic kidney disease (CKD), it has been established that disruption of monocyte and macrophage function can lead to chronic inflammation. Polarization of macrophages into the pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes results in distinct metabolic reprograming which corresponds to the progression and resolution of inflammation. In this review, we will discuss the role of the mitochondrion in monocyte and macrophage function and how these cells specifically influence the pathophysiology of atherosclerosis and CKD. We propose that assessing monocyte bioenergetics in different disease states could (1) enhance our understanding of the energetic perturbations occurring in systemic inflammatory conditions and (2) aid in identifying therapeutic interventions to mitigate these disorders in patients. © 2014 Elsevier Ltd.