Lipid-based nanoparticles (LNPs) hold great promise as delivery vectors in the treatment of cancer, inflammation, and infections and are already used in clinical practice. Numerous strategies based on LNPs are being developed to carry drugs into specific target sites. The common denominator for all of these LNPs-based platforms is to improve the payloads' pharmacokinetics, biodistribution, stability and therapeutic benefit, and to reduce to minimal adverse effects. In addition, the delivery system must be biocompatible and non-toxic and avoid undesirable interactions with the immune system. In order to achieve optimal benefits from these delivery strategies, interactions with the immune system must be thoroughly investigated. This report will center on the interactions of LNPs with different subsets of leukocytes and will detail representative examples of suppression or activation of the immune system by these carriers. By understanding the interactions of LNPs with the innate and the adaptive arms of the immune system it might be possible to attain improved therapeutic benefits and to avoid immune toxicity.