Integrase of phage fC31 catalyses the homologous recombination between Streptomyces attachment site attB and the phage attachment site attP. Meanwhile, this integrase can mediate integration of attB-containing donor plasmids into the pseudo attP sites in eukaryotic genomes by a site-specific manner and resulting long-term and robust expression of integrated genes. Nowadays, fC31 integrase system is becoming a potential tool for genome modification, gene therapy and transgenic research. Recent progress of fC31 integrase system in integration mode in mammalian genomes, efficiency improvement and researches concerned on transgenic safety were summarized in this review.