This paper critically reviews the current evidence of research in biomedical applications of selenium nanoparticles (SeNPs) and their effects at cellular and tissue levels. In recent years, interest in SeNPs as a natural trace element nanomaterial for nanomedicine has resulted in a number of studies evaluating their bioactivities, such as anticancer, antimicrobial, and antioxidant properties. Significant data have been generated to demonstrate the effectiveness of SeNPs alone or in combination with other reagents. Their activities are demonstrated through in vitro and in vivo experimentation; yet, the levels of efficacy need to be improved, particularly when compared with those of pharmaceutical drugs (such as antibiotics and cytotoxic chemotherapeutic drugs). However, promising evidence suggests decreased toxicity when using SeNPs, and more importantly their ability to perform as an interfacing biomaterial with cells and tissues. SeNPs have demonstrated unique antibacterial properties: they inhibit bacterial adhesion, growth, and/or quorum sensing and as a result prevent biofilm formation on medical devices, to name a few. Therefore, as with other nanomaterials, SeNPs warrant further study as part of the biomaterial-based therapeutic toolkit as an alternative to traditional pharmaceutical agents. This paper will provide a succinct review of recent studies on SeNPs to critically assess the findings in the light of effectiveness, particularly highlighting the roles of the cellular interface. Finally, an outlook of the potential of SeNPs will be presented to highlight the need for more intensive studies of material stability, mechanistic understanding at subcellular levels, and investigations into their combinational and/or synergistic effects with other bioactive reagents including pharmaceutical drugs.