(i) Uptake of some biguanides, such as metformin, is dependent on specific transport molecules such as OCT1; other biguanides, such as phenformin, are more lipophilic and less dependent on active transport. (ii) Biguanides can be actively excreted, for example by multidrug and toxin extrusion (MATE) proteins. (iii) Biguanides are not homogeneously distributed within the cell; the mitochondrial membrane potential promotes increased uptake of biguanides, and mitochondria have the highest concentration. This is important, as key targets such as respiratory complex I, are in the mitochondria. Mitochondrial actions of biguanides reduce oxidative phosphorylation, resulting in decreased cellular ATP (iv), decreased NAD⁺ (v), and other derangements in mitochondrial metabolism. The reduction in ATP generation from oxidative phosphorylation leads to a compensatory increase in glucose uptake (vi) and glycolysis, with increased lactate secretion (vii). However, especially if glucose concentrations are limiting, this compensation is not sufficient to restore ATP to baseline levels. (viii) Therefore, if AMPK and its effectors are functional, AMPK activation results in reductions in energy expenditure and anabolic processes, leading to an antiproliferative (but potentially prosurvival) effect. (ix) On the other hand, in cancers with loss of function of AMPK or its key effectors, energy expenditure is not reduced despite reduced energy supply, leading to an energetic crisis.