Synthesis and regulation of lipid levels and identities is critical for a wide variety of cellular functions including structural and morphological properties of organelles, energy storage, signaling, as well as stability and function of membrane proteins. Proteolytic cleavage events regulate and/or influence some of these lipid metabolic processes, and as a result, help modulate their pleiotropic cellular functions. Proteins involved in lipid regulation are proteolytically cleaved for the purpose of their re-localization, processing, turnover, quality control, amongst others. The scope of this review will cover proteolytic events governing cellular lipid dynamics. Starting with the classic example of sterol regulatory element-binding proteins (SREBPs), our focus will then shift to the mitochondrion, where a range of proteolytic events are critical for normal mitochondrial phospholipid metabolism and enforcing quality control therein. Recently, mitochondrial phospholipid metabolic pathways have been implicated as important for the proliferative capacity of cancers. Thus, the assorted proteases that regulate, monitor, or influence the activity of proteins important for phospholipid metabolism represent attractive targets to be manipulated for research purposes and clinical applications.