Lipid droplets (LDs) commonly accumulate in non-adipocyte cells during the development of many metabolic and aging-related diseases. This accumulation is not only a hallmark of disease but likely plays a role in disease etiology. Yet, the mechanisms through which LDs drive cellular dysfunction have not been fully elucidated. The presentation will discuss two ongoing projects that provide plausible mechanisms through which LDs lead to cellular dysfunction and disease development. In particular, the role of LDs in the regulation of genomic stability and cellular senescence will be presented along with data defining a mechanism through which LDs drive inflammation. Together, these studies define pathways through which alterations in LD dynamics and signaling influence disease pathophysiology.