A wealth of evidence indicates that high-density lipoprotein assumes the unique antiatherosclerosis and other cardioprotective properties. Based on that, HDL-C has been considered as a promising therapy target to reduce the cardiovascular diseases. Recombinant HDL (rHDL) and apolipoprotein mimetic peptides emerge in recent years and have great potential in the future. Here we discussed the pleiotropic therapeutic effect of rHDL based on the effects of atherogenic, angiogenesis, platelet, vascular, and Alzheimer's disease. On the other hand, rHDL not only plays the key role as the major protein component of HDL, it is also used as a nanovector in antiatherosclerotic, antitumor, cardiovascular diagnosing and other therapeutic areas. Synthetic apolipoprotein mimetic peptides like apoA-I and and apoE mimetics have undergone clinical assessment, and we have also reviewed the advances of clinical trials and gave an outlook for the therapy of rHDL and mimetic peptides.