Abstract The incidence of cardiogenic shock (CS) has increased remarkably over the past decade and remains a challenging condition with mortality rates of ∼50%. Cardiogenic shock encompasses cardiac contractile dysfunction; however, it is also a multiorgan dysfunction syndrome, often complicated by a systemic inflammatory response with severe cellular and metabolic dysregulations. Here, we review the evidence on the biochemical manifestations of CS, elaborating on current gold standard biomarkers and novel candidates from molecular signatures of CS. Glucose and lactate, both identified over a century ago, remain the only clinically used biomarkers in current predictive risk scores. Novel genomic, transcriptomic, and proteomic data are discussed, and a recently reported molecular score derived from unbiased proteomic discovery, the CS4P, which includes liver fatty acid-binding protein, beta-2-microglobulin, fructose-bisphosphate aldolase B, and SerpinG1 is comprehensively described. Recent advances in -omics technologies provide new insight into a more holistic molecular signature of CS. Thus, we need to open new diagnostic and therapeutic avenues if we aim to improve outcomes.