It took >20 years to discover the family of proteases implicated in the activation and/or regulation of the activity of secretory proteins, including polypeptide hormones, growth factors and receptors. From 1990 to 2003 the 9 members of the proprotein convertase (PC) family were identified and shown to be phylogenetically ancient serine proteases related to bacterial subtilases and to yeast Kexin, now called Proprotein Convertases related to Subtilsin and Kexin (PCSK1-PCSK9). Because many growth factors, receptors, adhesion molecules, metalloproteinases, cytokines, etc., are produced as inactive precursors, PCSKs are critical "master switches" that regulate when and where these proteins become active. Several PCSK family members have been linked to cardiovascular disease (CVD), but the "big four" in the CV space are PCSK9, PCSK7, Furin (PCSK3), and SKI-1/S1P (PCSK8) with others playing more indirect or emerging roles. This review will largely concentrate on the CVD implications of PCSK9 and PCSK7 that non-enzymatically regulate lipids levels. The prototypical proatherogenic convertase PCSK9 regulates LDL-cholesterol (LDLc) via targeting the LDLR for lysosomal degradation, but it also affects other receptors and inflammatory pathways. Beyond LDLc, PCSK9 is expressed in endothelial cells, vascular smooth muscle cells, and macrophages within plaques and promotes atherosclerosis via endothelial dysfunction, macrophage activation and inflammation, plaque progression/instability and thrombosis. In contrast, PCSK7 regulates triglycerides (TG) and lipids via a chaperone-like effect enhancing apolipoprotein B (apoB) and VLDL secretion. Finally, PCSK9 and PCSK7 regulate immune function by enhancing the activity of cytotoxic T-cells, and silencing both convertases provides in a synergistic protection against tumor growth and metastasis.