The advances in the pharmaceutical therapy on the aspects of efficacy, safety, and quality of the medicines available for the patients require the constant search for novel release systems. In this sense, there are the lipid nanoparticles (LN) of first and second generation: the solid lipid nanoparticles (SLN) and the nanostructured lipid carriers (NLCs), which are alternative systems that combine advantages of several colloidal carrying agents. Besides, the LN are prepared with ingredients considered as safe for the use in biological systems as they are physiologically compatible. This chapter brings a combination of information from the beginning of the development of these systems since the 1990s until modern studies, approaching the main preparation methods and also the LN evaluation as drug delivery systems through different application routes. In this approach, the great ease of production of these systems, using simple and easily scaling-up methods, such as the high-pressure homogenization (HPH), is observed. Thus, as they are nanostructured systems, it is really important to evaluate the intrinsic 316toxicity of the tiny size of these particles, especially when smaller than 100 nm for parenteral administration. In general, the LN are considered low toxicity formulation with a broad range of application where they may be hydrophilic or lipophilic; thus, they are being considered as highly versatile systems and promising to the future of medical therapy.