Leaf senescence is a sequence of biochemical and physiological events comprising the final stage in leaf development. It encompasses the period from a fully expanded mature state up to the death, thereby limiting longevity. The changes occurring during leaf senescence are very complex but highly regulated, and are genetically programmed with actions coordinated at the cellular, tissue, organ, and organism levels. A major breakthrough in our molecular understanding of this phenomenon has been achieved through the characterization of various mutants and senescence-associated genes, including regulatory genes. In particular, a genetic screening and assay system for leaf senescence has been well established in Arabidopsis, which led leaf senescence into the realm of genetic subject along with the rich genetic and genomic resources in this model plant. These advances have not only revealed the existence of a complex regulatory network of senescence-associated signaling pathways, but have also allowed us to postulate the molecular mechanisms for signal perception, execution, and regulation. The key regulatory genes identified to date encode a variety of proteins, including transcription regulators and signal-transduction proteins, regulators of protein degradation, proteins associated with phytohormone pathways, and regulators of metabolism. Elucidation of their roles in leaf senescence and analyses of senescence regulatory pathways, including systems-level approaches, will increase our knowledge of the networks involved in senescence activity.