Liquid–liquid phase separation (LLPS) and phase transitions (PT) of proteins, which include the formation of gel- and solid-like species, have been characterized as physical processes related to the pathology of conformational diseases. Nucleic acid (NA)-binding proteins related to neurodegenerative disorders and cancer were shown by us and others to experience PT modulated by different NAs. Herein, we discuss recent work on phase separation and phase transitions of two amyloidogenic proteins, i.e. the prion protein (PrP) and p53, which undergo conformational changes and aggregate upon NA interaction. The role of different NAs in these processes is discussed to shed light on the relevance of PSs and PTs for both the functional and pathological roles of these mammalian proteins. •Proteins involved in cancer and neurodegenerative diseases undergo phase transitions.•Nucleic acids modulate prion protein and p53 phase transitions.•PrP liquid droplets evolve to gel-like species depending on the interacting NA.•p53 higher-order structures participate on cancer-promoting activities through NA binding.