Retrovirus-derived gene transfer systems (retroviral vectors) are the most commonly used gene transfer tools in modern biology. They have been used to study various aspects of retroviral replication, the organization and function of oncogenes and other eucaryotic genes, and, recently, to transduce therapeutic genes to cure inborn errors of metabolism, cancer, AIDS, and many other diseases in man. Highly oncogenic retroviruses served as a model for the construction of artificial retroviral gene transfer systems. These viruses carry a non-viral gene in their genome in addition or substituting for viral protein coding sequences. The replication of such defective retroviruses depends on the presence of a wild-type-virus, which supplies all proteins in trans for particle assembly and infection of a new target cell. Thus, highly oncogenic retroviruses can be considered as naturally occurring gene transfer vectors. Following this principle, cell lines have been constructed which express retroviral protein coding sequences from plasmid DNAs and which contain a viral genome in which the protein coding sequences have been replaced with a gene of interest. This article describes the history, principles, and basic building blocks of first and modern retrovirus-derived gene transfer systems.