Numerous preclinical studies have demonstrated the efficacy of recombinant adeno-associated virus (rAAV) gene delivery vectors, and recent clinical trials have shown promising results. However, the efficiency of these vectors, in terms of the number of genome-containing particles required for transduction, is hindered by the need to convert the single-stranded DNA (ssDNA) genome into double-stranded DNA (dsDNA) prior to expression. This step can be entirely circumvented through the use of self-complementary vectors, which package an inverted repeat genome that can fold into dsDNA without the requirement for DNA synthesis or base-pairing between multiple vector genomes. The important trade-off for this efficiency is the loss of half the coding capacity of the vector, though small protein-coding genes (up to 55 kd), and any currently available RNA-based therapy, can be accommodated. The increases in efficiency gained with self-complementary AAV (scAAV) vectors have ranged from modest to stunning, depending on the tissue, cell type, and route of administration. Along with the construction and physical properties of self-complementary vectors, the basis of the varying responses in multiple tissues including liver, muscle, and central nervous system (CNS) will be explored in this review.