Calorie restriction (CR) remains the most well-established experimental intervention to delay the onset of ageing and age-associated disease(s). However, this is not a new phenomenon. The beneficial effects of CR have been well recognized since the early 1930s. It is only recently the interest in understanding the mechanism(s) behind the beneficial effects has gained momentum. Mitochondria are proposed to be the leading target for the CR-mediated effects, given the fact that mitochondria are the primary regulators of cellular energy and oxidative stress. Consistent with this theory, many mitochondrial components are damaged with ageing and age-related diseases. More importantly, mitochondrial dysfunction has been implicated in premature ageing syndromes such as Werner's syndrome. Thus, this makes mitochondria an attractive target for the modulation of both ageing and age-related diseases. In recent years, the study of the CR story has made great progress towards understanding how CR ameliorates mitochondrial dysfunction; however, much is still to be understood. This review will examine the role of five players in the CR story: the sirtuins, adenosine monophosphate (AMP)-activated protein kinase (AMPK), peroxisome proliferator-activated receptor (PPAR) coactivator-1alpha (PGC-1alpha), mammalian target of rapamycin (mTOR) and <i>pha-4</i>.