Mature fruit abscission in fleshy fruit is a genetically controlled process with mechanisms that, contrary to immature fruit abscission, have not been fully characterized. Here, we use pyrosequencing to characterize the transcriptomes of melon abscission zone (AZ) at three stages during AZ-cell separation in order to understand abscission control at an early stage of AZ-activation. The results show that by early induction of abscission, the melon AZ exhibits major gene induction, while by late induction of abscission, melon AZ shows major gene repression. Analysis of gene expression from these AZs reveals that a sequential induction of cell-wall-degrading genes is associated with the upregulation of genes involved in endo and exocytosis, and a shift in plant hormone metabolism and signaling genes during abscission. This is accompanied by transcriptional activity of small-GTPases and synthaxins together with tubulins, dynamins, V-type ATPases and kinesin-like proteins potentially involved in abscission signaling. Early events are potentially controlled by down-regulation of MADS-box, AP2/ERF and Aux/IAA transcription-factors, and up-regulation of homeobox, zinc finger, bZIP, and WRKY transcription-factors, while late events may be controlled by up-regulation of MYB transcription-factors. Overall, the data provide a comprehensive view on abscission in fleshy fruit, identifying candidate genes and pathways associated with early induction of fruit abscission. Our comprehensive gene expression profile will be very useful for elucidating gene regulatory networks of the fruit abscission in fleshy fruit.