TMEM106B variants are genetically associated with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), and are considered a major risk factor for this disease. As TMEM106B may be involved in other pathologies such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), uncovering its cellular functions has become a priority. In this issue of The EMBO Journal, Schwenk et al (2014) combine loss-of-function experiments, live imaging and proteomics to unveil the physiological roles played by TMEM106B and its binding partner MAP6 in lysosomal function and transport.