Ripening is a highly programmed developmental process that confers economically important properties to fruit. Although the key roles of the phytohormone ethylene and related transcription factors have been well studied in the regulation of fruit ripening in the model fruit, tomato, melon (Cucumis melo L.) is also recognized as an attractive alternative model because of the co-existence of climacteric and non-climacteric types, as well as the availability of the whole genome sequence and other rich genetic resources. In climacteric melon, genetic evidence demonstrates that ripening-associated biochemical changes are brought about by both ethylene-dependent and -independent pathways. Recently, genome, transcriptome, metabolite, and systems biology studies that have employed high-throughput analytical technologies have further investigated the molecular basis of fruit ripening in melon. This chapter is intended to combine the previous and current knowledge about melon fruit ripening with a main focus on molecular mechanisms.