This paper presents open challenges and perspectives of propellant management for crewed deep space exploration. The most promising propellants are liquid hydrogen and liquid methane, together with liquid oxygen as an oxidizer. These fluids remain liquid only at cryogenic conditions, that is, at temperatures lower than 120 K. To extend the duration of space exploration missions, or even to enable them, the storage and refueling from a cryogenic on-orbit depot is necessary. We review reference missions, architectures, and technology demonstrators and explain the main operations that are considered as enablers for cryogenic storage and transfer. We summarize the state of the art for each of them, showing that many gaps in physical knowledge still need to be filled. This paper is based on recommendations originally proposed in a White Paper for ESA’s SciSpacE strategy.