"Classic" Kaposi's sarcoma (CKS) not related to HIV is a multifocal angioproliferative neoplasm that is linked to human herpesvirus. CKS is a cutaneous cancer frequently occurring with an indolent course. However, it can compromise the quality of life by causing pain, disfigurement and functional disability. For this reason, the main treatment goals are not only to reduce the cutaneous lesions but also to alleviate organ involvement and psychological stress by delaying disease progression and ultimately cure. This report summarizes systemic treatment options of CKS, including chemotherapy, immunotherapy and anti-HHV8 therapy. In addition, this review will focus on the recent understanding of carcinogenesis and consequently highlight potential "targeted" therapeutic interventions.