Abstract: Aging is associated with declines in health and physiological functions, leading to an increase in the number of many chronic diseases. One of the critical pillars or underlying mechanisms of aging is cellular senescence. Senescence is a phenomenon in which cells lose the ability to proliferate under different cellular stress conditions, resulting in a state of stable cell cycle arrest. With age, senescent cells accumulate in various tissues where they contribute to loss of tissue homeostasis, aging, and age-related diseases through their inflammatory senescence-associated secretory phenotypes (SASPs). Senotherapeutics able to selectively eliminate senescent cells, termed senolytics, or suppress the detrimental SASPs, termed senomorphics, we have been demonstrated to improve age-associated comorbidities and aging phenotypes. To discover novel senotherapeutics translatable to promote healthy longevity,  we have leveraged drug screening and drug design strategies, and developed a series of novel senolytics and senomorphics. The studies of the therapeutic potential of four of these senotherapeutics using cell and mouse models of senescence and aging will be presented.