Recombinant retroviral vectors based upon simple gammaretroviruses, complex lentiviruses, or potentially nonpathogenic spumaviruses represent relatively well characterized tools that are widely used for stable gene transfer. Different members of the Retroviridae family have developed distinct and potentially useful features related to their life cycle. These natural differences can be exploited for specialized applications in gene therapy and could conceivably be combined to create future retroviral hybrid vectors, ideally incorporating the following features: an efficient, noncytopathic packaging system with low likelihood of recombination; serum resistance; an ability to pseudotype with cell-specific envelopes; high-fidelity reverse transcription before cell entry; unrestricted cytoplasmic transport and nuclear import; an insulated expression cassette; specific chromosomal targeting; and physiologic or regulated levels of transgene expression. We envisage that, compared to contemporary vectors, a hybrid vector combining these properties would have increased therapeutic efficacy and an enhanced biosafety profile. Many of the above goals will require the inclusion of nonretroviral components into vector particles or transgenes.