Chronic subdural hematoma pathophysiology has been extensively studied and discussed. In the last decades, optic and electron microscope observations have successfully described its histopathology and the ultrastructure of internal membranes. Moreover, recent biochemical studies have identified a number of important pathways involved in its development and evolution. Our aim was to review recent literature regarding histopathology, ultrastructure and biochemichal pathways and supply a unifying theory about chronic subdural hematomapathophysiology. The starting point of chronic subdural hematoma is a mechanical injury. The evolution of the pathology is due to the exclusive anatomy of the dura-arachnoid interface. This is a mechanically weak layer. Fibroblasts contained in this region produce an inflammatory reaction with neoangiogenesis and fibrinolysis. Biochemical pathways involved in these reactions is complex and could contain a number of pharmacological targets. The hematoma evolves in different stages thus recent outlooks consider chronic subdural hematomaas a dynamic process. One of the key points for a good outcome and a low recurrence rate may be the timing of the surgical treatment in relation of hematoma natural history. Surgery performed during active inflammatory stages may be less effective in terms of clinical outcome and recurrence rate.