In mammals, after a myocardial infarction episode, the damaged myocardium is replaced by scar tissue with negligible cardiomyocyte proliferation. Zebrafish, in contrast, display an extensive regenerative capacity, as they are able to restore completely lost cardiac tissue after partial ventricular amputation. Although questions about the early signals that drive the regenerative response and the relative role of each cardiac cell type in this process still need to be answered, the zebrafish is emerging as a very valuable tool to understand heart regeneration and to devise strategies that may be of potential value to treat human cardiac disease. Here, we performed a genome-wide transcriptome profile analysis focusing on the early time points of zebrafish heart regeneration and compared our results with those of previously published data. Our analyses confirmed the differential expression of several transcripts and identified additional genes whose expression is differentially regulated during zebrafish heart regeneration. We validated the microarray data by conventional and/or quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). For a subset of these genes, their expression pattern was analyzed by in-situ hybridization and shown to be upregulated in the regenerating area of the heart. Our results offer new insights into the biology of heart regeneration in the zebrafish and, together with future experiments in mammals, may be of potential interest for clinical applications.