For inherited cardiomyopathies, abnormal sensitivity to intracellular calcium (Ca2+), incurred from genetic mutations, initiates subsequent molecular events leading to pathological remodeling. Here we characterized the effect of β-adrenergic stress in familial dilated cardiomyopathy (DCM) using human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) from a patient with RBM20 DCM. Our findings suggest that β-adrenergic stimulation accelerated defective Ca2+ homeostasis, apoptotic changes and sarcomeric disarray in familial DCM hiPSC-CMs. Furthermore, pharmacological modulation of abnormal Ca2+ handling by pre-treatment with β-blocker, carvedilol, or Ca2+-channel blocker, verapamil, significantly decreased the area under curve, reduced percentage of disorganized cells, and decreased TUNEL positive apoptotic loci in familial DCM hiPSC-CMs following β-adrenergic stimulation. These translational data provide patient-based in vitro analysis of β-adrenergic stress in RBM20–deficient familial DCM hiPSC-CMs and evaluation of therapeutic interventions to modify heart disease progression, which may be personalized but more importantly generalized in the clinic.