We review the lessons from a case of combined heart and liver transplantation (CHLT) 20 years post-operatively from the molecular to clinical levels. CHLT replaces cardiac function and provides a new source of Low density lipoprotein-receptors (LDL-R) known to be deficient in Familial Hypercholesterolaemia. Little is known of the long-term outcomes of this strategy. We review the lessons from a case of CHLT 20 years post-operatively, which illustrate the successful transition from the molecular understanding of the pathophysiology to the clinical therapy. Most importantly, there is evidence that transplantation of multiple organs from a single donor promotes operational tolerance, especially in the case of the liver. This lady presented in severe heart failure with advanced atherosclerotic disease resulting in coronary artery and aortic valve stenosis. The serum LDL-C concentration of 13 mmol/L was refractory to conventional therapy. Genetic analysis showed a large deletion on one allele of the LDL-R, and a mutant allele that produced a receptor which was delayed in its transport to the cell membrane and had 10% of normal receptor activity. The patient had a normalised lipid-profile directly after CHLT (2.1 mmol/L), and this has remained stable since the time of operation. Apart from a minor episode of cardiac rejection at 3 weeks post-CHLT, the patient has had excellent heart and liver function throughout. This patient has not experienced any signs of rejection, despite only low-dose immunosuppression. We review what we have learnt from this case at the molecular and clinical levels.