Diagram of selected signaling effectors or signaling pathways that underlie cardiac hypertrophy or the transition to heart failure, with a special emphasis on immediate translational potential given the pharmacologic agents in development or clinical trials for other disorders. The diagram is also segregated into compartments in the cardiomyocyte, from receptors to second messengers to effector kinases. Some pathways lead to alterations in contractility and/or gene expression. The individual signaling mediators are discussed in the text. The diagram also depicts different therapeutic options based on known pharmacologic agents or gene therapy approaches. Green indicates drugs that are FDA approved, although not necessarily for cardiovascular indications. Red indicates treatments that are currently in phase 1 and 2 clinical trials, but again, not necessarily for cardiovascular indications. Blue indicates targets that have been identified in animal models and might be translated into phase 1 and 2 clinical trials with investigational compounds. NFAT, MEF2, and GATA4 are well-known cardiac-acting transcription factors that affect cardiovascular stress responsiveness. GPCR-BA, G-protein coupled receptor biased agonist, biased toward G-protein signaling; β-arrestin-BA, β-arrestin biased agonist. AC, adenylyl cyclase; ACE, angiotensin-converting enzyme; β-AR, β-adrenergic receptor; ARB, angiotensin receptor blocker; GC, guanylate cyclase; β-ARK-CT, β-adrenergic receptor kinase carboxyl terminus; NPR, natriuretic peptide receptor; PLC, phospholipase C; PLN, phospholamban; I-1, PP1 inhibitor 1; RYR2, ryanodine receptor 2; SERCA, sarcoplasmic reticulum Ca²⁺ ATPase. Dotted lines indicate indirect pathways.