Although many students of island biogeography consider the midriff islands one of the world’s last major refuges of pristine desert-island biota, humans have been a part of that ecosystem for possibly 10,000 years or more. Humans have long affected the terrestrial and inshore marine biota, but the most serious injuries they have caused apparently began in the mid- to late nineteenth century with the start of guano mining on Patos, Rasa, and San Pedro Mártir islands. Since then, most of the major human impacts affecting the Midriff are related to rapid population growth in northwestern Mexico and increasing demands for the Midriff’s fishery and tourist resources. This chapter offers both historical and ecological perspectives on the human occupancy of the Midriff, so that a cultural-historical foundation will be available for ecological studies in the region as well as for land-use planning and conservation. The Midriff, located between 28° and 29°45´N and 112° and 114°W, includes the coasts of Lower California and Sonora and 39 islands and islets. Tiburόn, with an area of 1223.53 km2 and a maximum elevation of 1219 m, and Ángel de la Guarda, with an area of 936.04 km2 and a maximum elevation of 1315 m, are among the largest and most mountainous islands of Mexico. The other major islands of the Midriff, in order of decreasing size, are San Esteban (40.72 km2), San Lorenzo (33.03 km2), Smith (Coronado) (9.13 km2), San Lorenzo Norte (Las Ánimas) (4.26 km2), San Pedro Mártir (2.9 km2), Mejía (2.26 km2), Partida Norte (1.36 km2), Dátil (Turner) (1.25 km2), Alcatraz (Tassne or Pelícano) (1.2 km2), Salsipuedes (1.16 km2), Estanque (Pond) (1.03 km2), Rasa (0.68 km2), and Patos (0.45 km2) (Murphy, unpublished data). The entire region is extremely arid, and Tiburón is the only island that has permanent potable water, found in a few springs or in tinajas, although several tinajas on Ángel de la Guarda may contain water for long periods. The only island permanently inhabited since initial European contact is Tiburón, the historic stronghold of the Seri Indians or Comcáac, once a seminomadic, nonagricultural, seafaring, hunting, fishing, and gathering people.