I loved Upstairs, Downstairs . . . you identify with the downstairs people while vicariously enjoying the life of the upstairs people. —Alistair Cooke, Host of Masterpiece Theatre Upstairs, Downstairs was beloved by a generation of Americans who became entranced by this classic story of an upstairs Edwardian family and its downstairs household. The series chronicled the daily repartee and tangled relationships between the upstairs and downstairs contingents, a tale laced with all of the ingredients of human complexity. Despite their diverse perspectives and backgrounds, the lives at 165 Eaton Place became entwined by their core values, conserved traits, and the shared challenges of the day. In terms of human biology, Upstairs, Downstairs was a classic saga of the interplay between genes and environment. In the family of human cardiomyopathies, another complex story is unfolding, this time around the divergent backgrounds and perspectives of clinical cardiology and molecular genetics. In this cardiological version of Upstairs, Downstairs, the theme is Genotype, Phenotype, and the initial storyline revolves around the precept that the primary determinant of the clinical phenotype is the molecular genotype. The clinical viewpoint has been underpinned by noninvasive analyses that can quantitatively assess differences in chamber volume, wall thickness, hypertrophy, systolic versus diastolic dysfunction, and outflow tract obstruction, leading to three clinical subtypes: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM). The molecular viewpoint has been driven by: 1) the discovery of diverse cardiomyopathic genotypes, resulting in a detailed examination of the differential phenotypic effects of mutations in a myriad of sarcomeric and cytoskeletal genes, 2) cataloguing the effects of missense mutations by the severity of the charge change within a given disease gene, 3) evaluating differences between haploinsufficiency and missense mutations, and 4) correlating these diverse disease genotypes with differences in the severity, time of onset, and diversity of the cardiomyopathy phenotype. The theme of this early script is that there may be a specific set of molecular pathways