Apolipoprotein E (apoE) is a crucial protein in lipid metabolism, playing a key role in the transport and catabolism of lipoproteins. ApoE is involved in the formation of lipoproteins responsible for transporting cholesterol and triglycerides in the bloodstream. Lipoproteins can be classified into several categories, including chylomicrons, low-density lipoproteins (LDL), and high-density lipoproteins (HDL), each with specific functions. The interaction between apoE and these lipoproteins is essential for regulating lipid metabolism and cholesterol homeostasis, impacting cardiovascular and neurological health. Docking and molecular dynamics are essential tools in scientific research. In this chapter, we highlight the up-to-date methods and research strategies in silico for deciphering the apoE complex dynamic interactions with plasma lipoproteins and other molecular domains for unfolding novel pharmacological targets for successful therapies in precision medicine.