As new studies demonstrate that lower levels of low-density lipoprotein cholesterol (LDL-C) reduce cardiovascular disease, and as goals for LDL-C in high-risk individuals are reduced further and further, reaching those goals becomes more difficult for a significant percentage of the population. New therapeutic approaches to lower LDL-C would, therefore, be advantageous, particularly in those who are most likely to suffer cardiovascular disease-associated morbidity and mortality. Mouse and human genetic models suggest that decreasing hepatic apolipoprotein B (apoB) production may be a therapeutic approach for the treatment of dyslipidemia. Because antisense oligonucleotides naturally distribute to the liver and can specifically inhibit synthesis of proteins from their messenger RNAs, antisense oligonucleotides represent a potential approach for decreasing the biosynthesis of apoB, and thereby, the production of both very low density lipoprotein (VLDL) and LDL. Newly developed apoB antisense approaches have produced results in animal models and humans, providing proof of concept regarding reductions in LDL-C concentrations. Surprisingly, despite prior experience with inhibitors of microsomal triglyceride transfer protein, which also inhibits the secretion of VLDL, apoB antisense-mediated reduction in VLDL secretion does not appear to cause marked steatosis. The mechanisms whereby two different approaches for inhibiting apoB and triglyceride secretion have different effects on hepatic triglycerides are currently being examined.