This review shows the most common and promising strategies to generate colloidally stable silica nanoparticles (NPs) in simulated biological fluids and sheds light on the latest advances in producing degradable silica-based structures. Silica NPs can be synthesized in a wide variety of morphologies, porosity levels, and sizes. This versatility makes silica NPs one of the most promising nano-platforms for imaging and disease treatment. Nonetheless, biological barriers can decrease the success of translating them for therapeutic applications since the media composition can induce their colloidal stability loss. It can, consequently, lead to the NPs aggregation and affect their degradation profile. The interplay between NPs aggregation and degradation has been scarcely explored in the literature when biological fluids are seriously taken into account. Herein we discuss the theory behind the colloidal stability of silica NPs, the processes leading to their aggregation, and some strategies to overcome this issue (mainly focused on NPs surface functionalization). Furthermore, we addressed the main issues that affect the degradability of NPs in biological fluids, and explored some strategies, such as chemical surface modification, which are able to tune these degradation-driven profiles. Thus, the understanding of the silica NPs behavior in body fluids is essential for the approval of nanomedicines and, therefore, more investigations concerning the dynamics, thermodynamics, biological response, and structural parameters of silica-based NPs are of utmost importance.