Cardiovascular disease remains the leading cause of morbidity and mortality globally. The disease is largely controlled with interventions managing atherogenic lipids including LDL and triglycerides. However a number of studies have shown that increasing HDL levels is likely to provide better outcomes for patients suffering from this disease. There has been an extensive research effort into understanding how HDL levels are regulated in the body and which pathways can be targeted therapeutically. The HDL metabolic pathway is however overwhelmingly complex. This has provided only limited success in trialing drugs designed to raise HDL. To add to the complexity HDL itself is a heterogeneous population of particles and there is controversy surrounding which HDL particle is the most cardio-protective. In addition there is varying opinions on which of the HDL cellular receptors are more important in humans (as opposed to what has been discovered in mice) in regulating these effects. In this article we explore the evidence for and against using the currently suggested methods of raising HDL and provide some evidence for how the adverse effects of these drugs could be corrected.