## 1 Introduction  
Genetically modified animals can be very useful tools for biomedical research. They are defined animals whose DNA has been altered using genetic engineering techniques, which include transgenic (carrying exogenous gene), knockout (disrupted endogenous gene by gene targeting), and knock-in (inserted gene sequence at a particular locus by gene targeting). Since the first birth of a transgenic mouse produced by pronuclear microinjection in 1980 [1], numerous genetically modified animals have been generated. In the biomedical research field, the mouse is the most used species for genetic modifications because of well-developed genetic engineering techniques that can produce not only transgenic, but also knockout animals by gene targeting techniques using embryonic stem (ES) cells [2]. In fact, various genetically modified murine models have been produced, which have strongly contributed to the progress of biomedical science. The mouse is one of the most useful laboratory animals, but it may not be omnipotent. Some physiological features of mice are quite different from those of humans, such as lipid metabolism [3; 4; 5]. Therefore, the mouse may not be suitable for research of lipid metabolism and atherosclerosis. To extrapolate findings from animal experimentation to humans, it is essential to choose an appropriate species that conforms to the purpose of the study. Therefore, the development of genetically modified non-murine models has been desired in several research fields where the mouse is considered as unsuitable.  
In 1985, the first production of a transgenic rabbit was reported by [PERSON] et al. [6]. To date, many transgenic rabbits have been generated and used as both human disease models and bioreactors that produce valuable physiologically active substances in their milk [3; 4; 7; 8; 9; 10]. However, in comparison with mice, the transgenic efficiency when using pronuclear microinjection is low and the production of knockout rabbits is difficult because ES cells have not been established for gene targeting in the rabbit [8; 11]. These problems limit the use of genetically modified rabbits as human disease models. Therefore, studies to improve the productive efficiency of transgenic rabbits [12; 13; 14; 15; 16] and establish rabbit ES cells [17; 18] have been conducted for a long time. The emergence of novel genome editing technology such as Zinc finger nuclease (ZNF), transcription activator-like effector nuclease (TALEN), and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), have changed production of genetically modified animals including the rabbit [19; 20; 21]. These techniques have revolutionized gene engineering technology because knockout animals can be produced easily with high efficiency by these techniques without ES cells. The first knockout rabbit generated by genome editing technology using ZFN was reported in 2011 [19]. After production of a knockout rabbit by the CRISPR/Cas9 system in 2014 [21], the number of reports of knockout rabbits for human disease models has increased rapidly [22; 23; 24; 25; 26; 27]. The use of genetically modified rabbits will expand to various purposes in biomedical research, although they have been limited to only transgenic use for a long time.  
Transgenic rabbits as human disease models have shown utility in several research fields in which the mouse is unsuitable as a model animal or as a superior model to the mouse, and they fulfill the need for a medium-sized animal between small rodents to humans for translational research. In this review, we introduce the unique features of the rabbit as a laboratory animal, the current status of their development and use, and future perspectives of transgenic rabbit models for human diseases.