The application of nanoparticles for medical purposes has made enormous strides in providing new solutions to health problems. The observation that plant virus-based nanoparticles (VNPs) can be repurposed and engineered as smart bio-vehicles for targeted drug delivery and imaging has launched extensive research for improving the therapeutic and diagnostic management of various diseases. There is evidence that VNPs are promising high value nanocarriers with potential for translational development. This is mainly due to their unique features, encompassing structural uniformity, ease of manufacture and functionalization by means of expression, chemical biology and self-assembly. While the development pipeline is moving rapidly, with many reports focusing on engineering and manufacturing aspects to tailor the properties and efficacy of VNPs, fewer studies have focused on gaining insights into the nanotoxicity of this novel platform nanotechnology. Herein, we discuss the pharmacology of VNPs as a function of formulation and route of administration. VNPs are reviewed in the context of their application as therapeutic adjuvants or nanocarrier excipients to initiate, enhance, attenuate or impede the formulation's toxicity. The summary of the data however also underlines the need for meticulous VNP structure-nanotoxicity studies to improve our understanding of their in vivo fates and pharmacological profiles to pave the way for translation of VNP-based formulations into the clinical setting. Display omitted •Plant viruses and their virus-like particles have been recognized as platform technologies for applications in nanomedicine.•Plant virus-based nanoparticles (VNPs) can be repurposed and engineered as smart bio-vehicles for targeted drug delivery and imaging; plant VNPs also find applications in vaccines and immunotherapy.•Given the growing body of data that indicate that plant VNPs are promising high value nanocarriers with potential for translational development, it is critical to gain in-depth understanding of their pharmacology to further advance the field.•The pharmacology of VNPs as a function of formulation and route of administration is discussed; most studies commonly reported no overt toxicity in vitro or in vivo; however, majority of these studies focused on routine cell viability assays as well as histopathological and haematological explorations; with no insights from extensive organ-function investigations.•Data highlight the potential for VNPs to impact disease management and treatment, but also underline the need for meticulous VNP structure-nanotoxicity studies to improve our understanding of their in vivo fates and pharmacological profiles to pave the way for translation of VNPs into the clinic.