Over the last decades, gene therapy has emerged as a pioneering therapeutic approach to treat or prevent several diseases. Among the explored strategies, the short-term silencing of protein coding genes mediated by siRNAs has a good therapeutic potential in a clinical setting. However, the widespread use of siRNA will require the development of clinically suitable, safe and effective vehicles with the ability to complex and deliver siRNA into target cells with minimal toxicity. Lately, dendrimers have gained considerable attention as non-viral vectors in nucleic acid delivery due to their unique structural characteristics (globular, well defined and highly branched structure, multivalency, low polydispersity and tunable nanosize), along with their relevant capacity to complex and protect nucleic acids in compact nanostructures, which can be functionalized with targeting moieties in order to get cell specificity. Here, we present an overview of the state-of-the-art of the most significant and recent advances on the use of dendrimers as siRNA delivery vectors, with particular focus on the in vivo applications. We will cover the use of different dendrimers, distinct administration routes, toxicity issues, as well as the target tissue or disease, highlighting the potential of dendrimers as nanocarriers for therapeutic and biomedical applications.The authors acknowledge the financial support of the Fundo para a Investigacao em Saude (INFARMED, project reference FIS-2015-01_CCV_20150630-88), as well as the FEDER funds through the Programa Operacional Competitividade e Internacionalizacao - COMPETE 2020 and the Portuguese funds through FCT - Fundacao para a Ciencia e a Tecnologia in the frame of the project POCI-01-0145-FEDER-016639 (reference PTDC/CTM-NAN/3547/2014). V. Leiro is supported by the project NORTE-01-0145-FEDER-000012, financed by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). S.D. Santos is supported by FCT (SFRH/BPD/109297/2015). We thank Joao Pedro Garcia for his contribution to the dendriplex picture
