Left ventricular hypertrophy (LVH) is one of the most common cardiovascular diseases; the estimated prevalence is 20% in the general population. In spite of being one of the greatest independent risk factors for cardiovascular morbidity and mortality, it remains essentially untreated. In this chapter, we review the complex interplay of physiologic systems that give rise to pathologic hypertrophy and heart failure. We explore the hierarchy of intra- and intercellular signaling systems that converge to produce the hypertrophic phenotype. Lastly, we consider novel access points within these systems that may represent new therapeutic windows for pharmacologic intervention.