A secure cartridge-based storage system includes a set of read/write control electronics on a control board adapted to removably couple with each of a plurality of storage cartridges. For each individual storage cartridge, the read/write electronics are adapted to retrieve a unique device identifier from the storage cartridge; retrieve an encryption key stored on the control board in association with the unique device identifier; and utilize the encryption key to encrypt or decrypt data that is in transit to or from a target storage location on the storage media.