The greatest challenge on Santa Fe is to ensure that no invasive species become established. Of particular concern is the potential arrival of introduced rats. On all islands except for Santiago, the endemic rice rat became extinct following the arrival and establishment of the invasive Black Rat. Regular monitoring of the endemic rat population is critical, along with regular checks for the arrival of introduced rats. Goats were introduced to Santa Fe sometime prior to 1905. These were finally eliminated (over 3,000 animals) between 1964 and 1972, with the last three goats removed in 1974. The vegetation of Santa Fe recovered slowly until the El Niño of 1982-83, when excessive rainfall resulted in near complete recovery. The Little Fire Ant was discovered and eradicated in 1975 and again in 1988. Periodic checks are critical to ensure that this aggressive species never gets reestablished on this small island.

At the international workshop on giant tortoises in 2012, the decision was made to pursue the return of giant tortoises to Santa Fe. A thorough review of the literature and the genetics of the few museum fragments from Santa Fe tortoises, as well as an evaluation of the status of the tortoise population on Española Island, resulted in a decision by the Galápagos National Park Directorate to restore giant tortoises on Santa Fe using an analog or substitute species – the Española giant tortoise. After building exclosures in the tortoise release area to later evaluate the impact of tortoises on the vegetation, the first release of 201 young Española tortoises (ranging in age from 4-10 years) was completed in June 2015. Annual releases of juvenile tortoises are planned for the next ten years.