Reptiles are a rare model object for space research. However, some reptile species demonstrate effective adaptation to spaceflight conditions. The main scope of this review is a comparative analysis of reptile experimental exposure in weightlessness, demonstrating the advantages and shortcomings of this model. The description of the known reptile experiments using turtles and geckos in the space and parabolic flight experiments is provided. Behavior, skeletal bones (morphology, histology, and X-ray microtomography), internal organs, and the nervous system (morphology, histology, and immunohistochemistry) are studied in the spaceflight experiments to date, while molecular and physiological results are restricted. Therefore, the results are discussed in the scope of molecular data collected from mammalian (mainly rodents) specimens and cell cultures in the parabolic and orbital flights and simulated microgravity. The published data are compared with the results of the gecko model studies after the 12–44.5-day spaceflights with special reference to the unique peculiarities of the gecko model for the orbital experiments. The complex study of thick-toed geckos after three spaceflights, in which all geckos survived and demonstrated effective adaptation to spaceflight conditions, was performed. However, future investigations are needed to study molecular mechanisms of gecko adaptation in space.