Abstract While humans lack sufficient capacity to undergo cardiac regeneration following injury, zebrafish can fully recover from a range of cardiac insults. Over the past two decades, our understanding of the complexities of both the independent and co-ordinated injury responses by multiple cardiac tissues during zebrafish heart regeneration has increased exponentially. Although cardiomyocyte regeneration forms the cornerstone of the reparative process in the injured zebrafish heart, recent studies have shown that this is dependent on prior neovascularization and lymphangiogenesis, which in turn require epicardial, endocardial, and inflammatory cell signalling within an extracellular milieu that is optimized for regeneration. Indeed, it is the amalgamation of multiple regenerative systems and gene regulatory patterns that drives the much-heralded success of the adult zebrafish response to cardiac injury. Increasing evidence supports the emerging paradigm that developmental transcriptional programmes are re-activated during adult tissue regeneration, including in the heart, and the zebrafish represents an optimal model organism to explore this concept. In this review, we summarize recent advances from the zebrafish cardiovascular research community with novel insight into the mechanisms associated with endogenous cardiovascular repair and regeneration, which may be of benefit to inform future strategies for patients with cardiovascular disease. Graphical Abstract Graphical Abstract Zebrafish and human injury response linking-diagrams to represent the effects of tissues on one another. Epicardium: light green, Endocardium: dark green, Vasculature: blue, Myocardium: red, Lymphatics: purple, Inflammation: yellow, and Extracellular Matrix: orange. Zebrafish follow a highly integrated cardiac regenerative programme involving all cardiac tissues, illustrated above by the Zebrafish Injury Response linking diagram. This is in direct contrast to humans where ischaemic injury is predominantly followed by inflammation and extracellular matrix deposition, as illustrated in the Human Injury Response linking diagram, leading to permanent scarring. It is interesting to consider whether a full understanding of the efficient regenerative programme of the zebrafish could inform future heart regeneration studies in humans (Krzywinski MI, Schein JE, Birol I, Connors J, Gascoyne R, Horsman D, Jones SJ, Marra MA. Circos: An information aesthetic for comparative genomics. Genome Res 2009; 31:1639-1645).