Multifocal fibrosclerosis is an uncommon fibroproliferative systemic disorder with multiple manifestations. It can involve almost every organ with fibroblastic proliferation. The microscopic pathology of these disorders is similar, showing a fibrotic process infiltrated with blood vessels, lymphocytes, and plasma cells. It has been suggested that these disorders are all interrelated and are probably different manifestations of a common disorder of fibroblastic proliferation. More common presentations include mediastinal fibrosis, retroperitoneal fibrosis, orbital pseudotumor, Riedel thyroiditis, and sclerosing cholangitis. Less common are Dupuytren contracture, Peyronie disease, testicular fibrosis, and pancreatic fibrosis. Newer syndromes have been added to the list, including pseudotumor of the pancreatic head associated with obstructive jaundice, panhypopituitarism, cervical epidural pseudotumor, renal pseudotumor, and sclerosing lobulitis of the breast. Clinical presentations depend on the site of involvement. It may present as infiltrative mass lesions mimicking malignancies and causing local symptoms such as obstruction and compression, or constitutional symptoms. Imaging with a CT scan or an MRI can show the extent of the lesion. A biopsy is usually required to establish the diagnosis and to exclude malignancy.