Gene therapy is the “products that mediate their effects by transcription and/or translation of transferred genetic material and/or by integrating into the host genome and that are administered as nucleic acids, viruses, or genetically engineered microorganisms. The products may be used to modify cells in-vivo or transferred to cells ex-vivo prior to administration to the recipient". Generally, gene therapies must retain two main criteria: (a) they contain an active material consists of nucleic acids such as deoxyribonucleic acid (DNA) or small interfering ribonucleic acid (siRNA). These macro molecules have the ability to regulate, repair, replace, add, or delete a genetic sequence; (b) the therapeutic, prophylactic, or diagnostic effect of these molecules are related directly to its gene sequence they contain or to the product of gene expression of this sequence. Gene therapies are directed mainly to treat multiple incurables, debilitating, and genetic diseases which have never treated by small active ingredients. Comparing data of cancer, genetic diseases, and autoimmune diseases with other diseases or to the actual number in the last decade reflects the obvious failure of conventional therapies in the treatment or controlling these diseases. However, the therapeutic effect of these macro molecules is hampered by higher sensitivity, lower stability, non-specific biodistribution, and lower cell permeability. PEGylated lipoplexes are the most common gene delivery non-viral based systems for transferring macromolecules such as DNA. Whatever the immune responses to PEGylated lipoplexes could limit their efficient contribution. In this review, immune responses to PEGylated lipoplexes were studied in details.