Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, is characterized by the death motor neurons leading to paralysis, muscle waste and death, usually within 2-5 years after clinical onset. We generated the first Drosophila model of ALS and showed that these flies exhibited motor disabilities, aggregate formation, synaptic dysfunction, neuronal degeneration, premature death-remarkably mimicking the human disease. Over the past few years, we have exploited and implemented this ALS Drosophila model to uncover novel and ‘surprising’ molecular mechanisms underlying disease pathogenesis. In particular, we used a combination of Drosophila genetics, extensive computational analyses and validation in post-mortem tissues of ALS patients to identify a number of disease modifying genes. These modifiers cluster in a diverse array of biological processes, including vesicular trafficking, cell proliferation and apoptosis and innate immunity. Surprisingly, the list of modifiers was mostly enriched for proteins linked to lipid droplet (LD) biogenesis and dynamics. Long considered to be mere depots for fat storage, LDs have now been redefined as functionally versatile organelles controlling lipid metabolism, oxidative stress and protein homeostasis.  LD biology in peripheral organs like the liver and heart has been well investigated, while LDs within the brain have received much less attention. We are currently focussing on dissecting the role of LD biology in ALS pathogenesis. In sum, these approaches should lead to the identification of novel and highly validated targets for therapeutic interventions.