In recent years, our understanding of the scope and diversity of protein post-translational modifications (PTMs) has rapidly expanded. In particular, mitochondrial proteins are decorated with an array of acyl groups that can occur non-enzymatically. Interestingly, these modifying chemical moieties are often associated with intermediary metabolites from core metabolic pathways. In this Review, we describe biochemical reactions and biological mechanisms that activate carbon metabolites for protein PTM. We explore the emerging links between the intrinsic reactivity of metabolites, non-enzymatic protein acylation, and possible signaling roles for this system. Finally, we propose a model of 'carbon stress', similar to oxidative stress, as an effective way to conceptualize the relationship between widespread protein acylation, nutrient sensing, and metabolic homeostasis.