Poorly water soluble (PWS) drugs lack from good oral absorption, which limits their oral administration, the most common drug delivery route. The design of appropriate innovative formulations for PWS drugs will allow for adequate bioavailability, reduction of the required dose and oral delivery of drugs that would otherwise need the parenteral route. Among the formulations under study, Nanostructured Lipid Carriers (NLCs), made of biocompatible mixtures of solid and liquid lipids, represent a good choice. NLCs enhance the apparent solubility and dissolution of PWS drugs in the gastrointestinal tract, and/or modulate the drug permeability and fate across the intestinal barrier, opening new perspectives in the field of innovative medicines for oral administration of PWS molecules. Recently, NLCs have also emerged as a promising anti-inflammatory drug delivery system for inflammatory bowel diseases. The present paper is focused on the state of the art of NLCs for oral delivery of PWS drugs. The design, the main preparation techniques and the mechanisms through the drug oral delivery is improved by NLCs are presented, highlighting the influence of the most relevant technological and formulation factors on the properties of the NLCs, which condition their efficacy as oral delivery formulations.