Unicellular diatom microalgae are a promising natural resource of porous biosilica. These microorganisms produce around their membrane a highly porous and extremely structured silica shell called frustule. Once harvested from living algae or from fossil sediments of diatomaceous earth, this biocompatible and non-toxic material offers an exceptional potential in the field of micro/nano-devices, drug delivery, theranostics, and other medical applications. The present review focused on the use of diatoms in the field of drug delivery systems, with the aim of presenting the different strategies implemented to improve the biophysical properties of this biosilica in terms of drug loading and release efficiency, targeted delivery, or site-specific binding capacity by surface functionalization. The development of composite materials involving diatoms for drug delivery applications is also described.