Calcium (Ca2+) is a universal regulator of various cellular functions. In cardiomyocytes, Ca2+ is the central element of excitation–contraction coupling, but also impacts diverse signaling cascades and influences the regulation of gene expression, referred to as excitation–transcription coupling. Disturbances in cellular Ca2+-handling and alterations in Ca2+-dependent gene expression patterns are pivotal characteristics of failing cardiomyocytes, with several excitation–transcription coupling pathways shown to be critically involved in structural and functional remodeling processes. Thus, targeting Ca2+-dependent transcriptional pathways might offer broad therapeutic potential. In this article, we (1) review cytosolic and nuclear Ca2+ dynamics in cardiomyocytes with respect to their impact on Ca2+-dependent signaling, (2) give an overview on Ca2+-dependent transcriptional pathways in cardiomyocytes, and (3) discuss implications of excitation–transcription coupling in the diseased heart.