Retrorsine (RTS) is a naturally occurring pyrrolizidine alkaloid (PA), isolated from Senecio retrorsus of South African origin. Retrorsine is a hepatotoxic Pyrrolizidine alkaloid which specifically inhibits the proliferation of hepatocytes and subsequently induces liver injury. The toxic effect of PAs has received plentiful clinical attention, yet the understanding of the mechanism of Retrorsine-induced hepatotoxicity is still limited. It has been reported that the CYPs mediated bioactivation is necessary for the toxicity of PAs and that CYP3A4 is the major isoform involved in the metabolism of Retrorsine. Together withCYP3A4, Organic cation transporter 1 mediates the liver-specific uptake of Retrorsine and plays an important role in RTS-induced hepatotoxicity. Retrorsine impairs liver regeneration after partial hepatectomy, not only by an S or G2/M phase block but also by a block located before the G1/S transition of the cell cycle. Treatment of rats with retrorsine, a pyrrolizidine alkaloid, results in a series of chronic and progressive hepatic lesions, including a long-lasting block in the cell cycle.