Since the first report in 1989, Metal-Organic Frameworks (MOFs) self-assembled from metal ions or clusters, as well as organic linkers, have attracted extensive attention. Due to their flexible composition, large surface areas, modifiable surface properties, and their degradability, there has been an exponential increase in the study of MOFs materials, specifically in drug delivery system areas such as infection, diabetes, pulmonary disease, ocular disease, imaging, tumor therapy, and especially cancer theranostics. In this review, we discuss the trends in MOFs biosafety, from "green" synthesis to applications in drug delivery systems. Firstly, we present the different "green" synthesis approaches used to prepare MOFs materials. Secondly, we detail the methods for the functional coating, either through grafting targeting units, poly(ethylene glycol) (PEG) chains or by using cell membranes. Then, we discuss drug encapsulation strategies, host-guest interactions, as well as drug release mechanisms. Lastly, we report on the drug delivery applications of nanoscale MOFs. In particular, we discuss MOFs-based imaging techniques, including magnetic resonance imaging (MRI), photoacoustic imaging (PAI), positron emission tomography (PET), and fluorescence imaging. MOFs-based cancer therapy methods are also presented, such as photothermal therapy (PTT), photodynamic therapy (PDT), radiotherapy (RT), chemotherapy, and immunotherapy.