Communication between cells is an important, evolutionarily conserved mechanism which enables the coordinated function of multicellular organisms. Heterogeneity within cell populations drive a remarkable network of cellular cross-talk that allows the heart to function as an integrated unit with distinct tasks allocated to sub-specialized cells. During diseases and aging, cells acquire an overt disordered state that significantly contributes to an altered cellular cross-talk and hence drive cardiac remodeling processes and cardiovascular diseases. However, adaptive mechanisms, and phenotypic changes in subpopulations of cells (e.g. reparative macrophages or fibroblasts) can also contribute to repair and regeneration. In this article, we review the cellular cross-talks between immune cells, endothelial cells, fibroblasts and cardiomyocytes that control heart failure by contributing to cardiac dysfunction and aging, or by mediating repair and regeneration of the heart after injury.