Solid lipid nanoparticles (SLNs), the spheroidal-shaped, colloids state lipophilic-natured, innovative nanoscale particulate materials, are being concurrently prepared by the quality-by-design approach for cellular and sub-cellular delivery of drugs and other payloads with facilitated physicochemical characteristics for targeted delivery. The delivery of drugs, other pharmaceuticals and biopharmaceutical materials, and genes to the diseased body organs, tissues, and cellular mass have been developed as promising nanocarriers for different high-incidence cancers and other disease therapies, including the Alzheimer’s, Parkinson’s, and tuberculosis. SLNs have evolved as favorable lipid-based formulation, and have served as oral and intravenous carriers that targeted the drug with stable and sterile transport, sustained delivery, controlled drug/payload deloading, and requisite biodistributions. SLNs advantages, shortcomings, and bottlenecks have been discussed with plausible remediation strategies. The laboratory-scale and bulk preparations, use of different lipids in various preparation, surface coatings, physicochemical properties of the final product, and characterization protocols are also encompassed, as are the routes of administrations, specific-sites-targeting, and on-site outreach with biocompatibility, bioavailability, and the absorption, distribution, metabolism, and excretion and pharmacokinetics, and pharmacodynamics inputs with relevance to the therapy. Plausible applications in complex and genetic disorders, and as personalized medicine, also of traditional and alternative medicine prospects, are also discussed.