The Picos de Europa mountain range in Northern Spain represents one of the most important alpine karsts in the world, containing a great concentration of deep limestone caves. It comprises Carboniferous limestones with thicknesses up to 2000 m and severely deformed by tectonic action. The structure and geological evolution, fracturing and Quaternary glaciation are among the main factors influenced the development of the caves. This paper proposes a speleogenetic model of the evolution, with an initial stage during which a Permo-Triassic cover provided semiconfinement for the entire carbonate series. Under these circumstances, the earliest known phreatic conduits were formed. Occasional relict sediments in them are related to the erosion of the cover. During the second stage, with the uplift of the massif, the cover was eroded and vadose conditions established; they were linked to glacial processes that intensified karstification, creating an unsaturated zone almost 2000 m thick. The karstification and vadose entrenchment in this zone are especially marked along preferential flow paths coinciding with pre-existing dolomitized and sulfide-mineralized fractures in the massif. These fractures may also have played a precursor role in the karstic evolution of the massif, as the source for more aggressive waters with a higher content of weak acids due to the oxidation of sulfides.