Krüppel-like factors (KLFs) are zinc finger transcription factors that share homology in three C-terminal zinc finger domains. KLF family members are expressed in most if not all tissues and have diverse roles in organismal development and cell differentiation, function, and death. The glomerular podocyte is particularly sensitive to mitochondrial dysfunction, as seen in various genetic disorders manifesting as progressive glomerulosclerosis. In this issue of the JCI, Mallipattu and coworkers show that KLF6 expression is reduced in mouse and human glomerular disease. Podocyte-specific deletion of Klf6 expression in mice leads to mitochondrial dysfunction and apoptosis, followed by glomerulosclerosis. This is the first demonstration that defective transcriptional regulation of nuclear-encoded mitochondrial genes can result in experimental glomerular disease.