Rates of atherosclerotic cardiovascular diseases (CVD) in the Western world have spectacularly decreased over the past 50 years. However, a substantial proportion of high-risk patients still develop heart attacks, strokes and valvular heart diseases despite benefiting from state-of-the-art treatments including lipid-lowering therapies. Over the past 10–15 years, it has become increasingly clear that Lipoprotein(a) (Lpa) is a critical component of this so-called residual risk. Genetic association studies revealed that Lp(a) is robustly, independently and causally associated with a broad range of cardiovascular and valvular heart diseases. Up to 1 billion people around the globe may have an Lp(a) level that places them in a high-risk category. Lp(a) is strongly associated with calcific aortic valve stenosis (CAVS), coronary artery disease (CAD), peripheral arterial disease (PAD) and to a lesser extent with ischemic stroke (IS) and heart failure (HF). Because of this strong association with cardiovascular and valvular heart diseases, Lp(a) even emerged as one of the most important genetic determinants of human lifespan and healthspan. Here, we review the evidence from the largest and most informative genetic association studies and prospective studies that have investigated the association between Lp(a) and human lifespan, healthspan, CVD, CAVS and non-cardiovascular diseases. We present Lp(a) threshold values that may be clinically relevant and identify other cardiovascular risk factors that may modulate the absolute risk of CVD in individuals with high Lp(a) levels. Finally, we identify key clinical and research questions that require further investigation to eventually and optimally reduce CVD risk in patients with high Lp(a) levels. Display omitted •Genetic studies identified lipoprotein(a) as one of the most important genetic determinants of human lifespan and healthspan.•Lipoprotein(a) is predominantly associated with calcific aortic valve stenosis and coronary artery disease (CAD).•Lipoprotein(a) is also causally associated with ischemic stroke, peripheral arterial disease and heart failure.•Clinical and lifestyle-associated factors may modify the absolute risk of CAD in individuals with high Lipoprotein(a) levels.•Randomized clinical trials evaluating the health impact of Lipoprotein(a)-lowering therapies are underway and eagerly awaited.