Background: The mountainous Wakhan and Pamir in northeastern Afghanistan is one of the most isolated yet inhabited places in Asia. It is home to the agropastoralist Wakhi and the last Afghan semi-nomadic Kyrgyz. We present a study of plant names and uses, along with comparisons of plant name etymology, origins of plant resources, intra- and intercultural exchanges and relations, and the relative availability of the known and used plants. Methods: The fieldwork was conducted as an expedition in the summer of 2010, and visited settlements and pastures in Upper Wakhan and Big and Little Pamir. Semi-structured group interviews, talks and observations gave initial data on names, uses and the relative availability of used plants, and provided foundation for individual interviews using an interview-herbarium containing vouchers of the 72 most frequently used plants or plant groups. Results: Wakhi and Kyrgyz plant names are recorded in western transcription, the new Wakhi alphabet, phonetically and in Cyrillic. The present study documents a large body of endemic, indigenous plant knowledge; on crops, fuel, fodder, cosmetics, dyes, vegetables, veterinary medicine, traditional medicines and other plant uses which sustain life in Wakhan and Pamir. Overall, the Wakhi use considerably more plants than the Kyrgyz, and their materia medica and use thereof is more complex. Although the Wakhi and Kyrgyz are close neighbours, there are few indications of direct knowledge transfer between them. Most shared plant uses are strictly necessary for survival in the mountains. While there are few differences between genders and cultural subgroups within the two cultures, the Wakhi and Kyrgyz exhibit great differences both in their total number of use-plants and the distance from which they obtain them. The agropastoralist Wakhi appear to have their basic needs for wild natural resources covered within half a days travel, while the relatively plant-derived environment of the high Pamir appears to have necessitated the nomadic Kyrgyz to adapt by developing uses and obtaining plants that are comparatively remote. Conclusion: The comparative differences in plant uses between the agropastoralist Wakhi and nomadic Kyrgyz appear to be accentuated by an environment at the extreme of what is humanly possible.