Frontotemporal lobar degeneration (FTLD) comprises diseases with a very diverging spectrum in regards to clinical presentation, genetics, and neuropathology. In 1892 Arnold Pick published the case of 71-year old male with progressive symptoms of aphasia, apathy, and dementia (Pick 1892). The pathological examination revealed cortical atrophy with emphasis on the left temporal lobe (Pick 1892). Pick described another case of a 60-year old male with progressive signs of negligence, apathy, apraxia, and dementia (Pick 1906). This patient had bilateral frontal cortical atrophy on pathological examination (Pick 1906). Both cases demonstrate the main clinical and pathological spectrums while at the same time pointing at the clinical and pathological heterogeneity. Leading clinical symptoms were language deficits and behavioral changes. Both cases showed selective cortical atrophy of the left temporal lobe and both frontal lobes while relatively sparing the parietal and occipital lobes. The frontal lobes harbor the prefrontal cortex with its three distinct parts that differ in phylogeny, assembly, connectivity and function: 1. dorsolateral convexity 2. medial part: anterior gyrus cinguli 3. limbic orbito-frontal cortex The dorsolateral convexity is important for the executive functions, i.e., anticipatory, analytical and imaginative thinking, as well as cognitive flexibility. The medial part is involved in attention, motivation, empathy, and emotion. The orbito-frontal cortex plays an important role in controlling impulses, emotions, and social behavior. The prefrontal cortex is closely connected with the sensory association cortices, the limbic system, and the basal ganglia. In the first part of this chapter, focus will be on clinical symptoms, diagnostics including neuropsychological and neuroimaiging findings, and therapy, while the second and third part will highlight recent findings in neurogenetics and neuropathology, respectively.