Frontotemporal lobar degeneration (FTLD) is characterized by progressive deterioration of frontal and anterior temporal lobes of the brain and often exhibits frontotemporal dementia (FTD) on clinic, in < 65-year-old patients at the time of diagnosis. Interdisciplinary approaches combining genetics, molecular and cell biology, and laboratory animal science have revealed some of its potential molecular mechanisms. Although there is still no effective treatment to delay, prevent, and reverse the progression of FTD, emergence of agents targeting molecular mechanisms has been beginning to promote potential pharmaceutical development. Our review summarizes the latest new findings of FTLD and challenges in FTLD therapy.