TRPML1, TRPML2 and TRPML3 belong to the mucolipin family of the TRP superfamily of ion channels. The founding member of this family, TRPML1, was cloned during the search for the genetic determinants of the lysosomal storage disease mucolipidosis type IV (MLIV). Mucolipins are predominantly expressed within the endocytic pathway, where they appear to regulate membrane traffic and/or degradation. The physiology of mucolipins raises some of the most interesting questions of modern cell biology. Their traffic and localization is a multistep process involving a system of adaptor proteins, while their ion channel activity possibly exemplifies the rare cases of regulation of endocytic traffic and hydrolysis by ion channels. Finally, dysregulation of mucolipins results in cell death leading to neurodegenerative phenotypes of MLIV and of the varitint-waddler mouse model of familial deafness. The present review discusses current knowledge and questions regarding this novel family of disease-relevant ion channels with a specific focus on mucolipin regulation and their role in membrane traffic and cell death. Since mucolipins are ubiquitously expressed, this review may be useful for a wide audience of basic biologists and clinicians.