Atherosclerosis is a major cause of disease-related mortality around the globe. The main characteristic of the disease is an accumulation of plaque on the arterial wall and subsequent erosion or rupture of some plaques. Atherosclerosis often leads to cardiovascular disease and such acute complications as myocardial infarction or ischaemic stroke due to thrombus formation. Most recent advances in atherosclerotic research state that the modifications of low- density lipoprotein (LDL) are one of the most significant stages in the disease initiation, and among these modifications desialylation is of particular interest. Sialic acids are widely expressed on all types of cells of many organisms and participate in numerous biological processes. Regarding atherosclerosis, sialidases that are responsible for the regulation of the sialic component of different molecules, are probably one of the most crucial enzymatic families. Sufficient sialylation of vascular endothelium defines its susceptibility to an atherogenic plaque formation. Moreover, the desialylation of LDL provokes an accumulation of cholesterol and lipids in the arterial walls. According to the multiple involvements of sialic acids and related enzymes, sialidases, in the initiation and development of atherosclerosis, the deeper understanding of their exact role, as well as cellular and molecular mechanisms, will allow creating more targeted and effective therapeutic and diagnostic approaches.