Retroviruses are a family of widespread small animal viruses that can cause a variety of neoplastic and immunosuppressive diseases. Murine leukemia viruses (MuLV) have been used as model systems to investigate virion and genomic RNA structure, viral replication and variability, and pathogenesis. Detailed knowledge of the genetic structure of MuLV and of the viral life cycle has led to the development of MuLV-derived retroviral vectors for gene transfer with potential applications in human gene therapy. In this review we have summarized the properties and functions of the 5' domain, called the leader, of MuLV genomic RNA. The 5' leader is formed of small interspersed and superimposed genetic elements involved in every step of the viral life cycle. In addition, the 3' domain of the leader encodes the N-terminal part of glycosylated forms of the GAG polyprotein, also named Gross cell surface antigen (GCSA or glycoGAG) which is essential for full spreading and pathogenic abilities of the virus in the animal. Therefore, the 5' leader of MuLV genomic RNA appears to be a very attractive model to study structure-function relationships of a small and multifunctional genetic domain in vitro, in cell culture and in the animal.