Leaf senescence constitutes the final stage of leaf development and is critical for plants' fitness as nutrient relocation from leaves to reproducing seeds is achieved through this process. Leaf senescence involves a coordinated action at the cellular, tissue, organ, and organism levels under the control of a highly regulated genetic program. Major breakthroughs in the molecular understanding of leaf senescence were achieved through characterization of various senescence mutants and senescence-associated genes, which revealed the nature of regulatory factors and a highly complex molecular regulatory network underlying leaf senescence. The genetically identified regulatory factors include transcription regulators, receptors and signaling components for hormones and stress responses, and regulators of metabolism. Key issues still need to be elucidated, including cellular-level analysis of senescence-associated cell death, the mechanism of coordination among cellular-, organ-, and organism-level senescence, the integration mechanism of various senescence-affecting signals, and the nature and control of leaf age.