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Cardiac glycosides (CGs) are compounds used for the treatment of cardiac failure which also display strong anti-cancer activity inducing impairment of cell proliferation or activation of cell death whether by apoptosis or autophagy. Despite the fact that the sodium/potassium (Na⁺/K⁺)-ATPase is a well-known target of CGs, its involvement in the anti-cancer effect of these compounds remains to be validated. Importantly, related intracellular sensor(s)/transducer(s) needs further characterization. We will discuss here key mechanisms activated by CGs including their ability to modulate the cell cycle and to regulate the expression of anti-apoptotic Bcl-2 family members, two so far marginally investigated events.