High-altitude Andean lakes (HAAL) are a treasure chest for microbiological research in South America. Their indigenous microbial communities are exposed to extremely high UV irradiation and to multiple chemical extremes (Arsenic, high salt content, alkalinity). Microbes are found both, free-living or associated into microbial mats with different degrees of mineralization and lithification, including unique modern stromatolites located at 3570 m above sea level. Characterization of these polyextremophilic microbes began only recently, employing morphological and phylogenetic methods as well as high-throughput sequencing and proteomics approach. Aside from providing a general overview on microbial communities, special attention is given to various survival strategies; HAAL's microbes present a complex system of shared genetic and physiological mechanisms (UV-resistome) based on UV photoreceptors and stress sensors with their corresponding response regulators, UV avoidance and protection strategies, damage tolerance and UV damage repair. Molecular information will be provided for what is, so far the most studied HAAL molecule, a CPD-Class I photolyase from Acinetobacter Ver3 (Laguna Verde, 4400 m). This work further proposes some strategies that make an appeal for the preservation of HAAL, a highly fragile environment that offers promising and ample research possibilities.