The Red Sea harbours approximately 25 deep-sea anoxic brine pools. They constitute extremely unique and complex habitats with the conjugation of several extreme physicochemical parameters rendering them some of the most inhospitable environments on Earth. After 50 years of research mostly driven by chemists, geophysicists and geologists, the microbiology of the brines has been receiving increased interest in the last decade. Recent molecular and cultivation-based studies have provided us with a first glimpse on the enormous biodiversity of the local microbial communities, the identification of several new taxonomic groups, and the isolation of novel extremophiles that thrive in these environments. This review presents a general overview of these unusual biotopes and compares them with other similar environments in the Mediterranean Sea and the Gulf of Mexico, with a focus on their microbial ecology.