The Atacama Desert of northern Chile is considered one of the most arid and extreme environment on Earth. Its core region was described as featuring "Mars-like" soils that were at one point deemed too extreme for life to exist. However, recent investigations confirmed the presence of diverse culturable actinobacteria. In the current review, we discuss a total of 46 natural products isolated to date representing diverse chemical classes characterized from different actinobacteria isolated from various locations in the Atacama Desert. Their reported biological activities are also discussed.