The last decade has seen an impressive increase of the research dedicated to the biomedical applications of low temperature plasmas, especially with plasma sources working at atmospheric pressure. In this new trend, beside decontamination/sterilization and surface treatment that have already a quite long story through low-pressure plasma research and developments, medical applications are tacking an increasing place underlined by the actual numerous clinical trials. Medical applications of low temperature plasmas now concern a very wide range of domains, including primary haemostasis and blood coagulation, dental care, skin decontamination and hygiene, wound and ulcer treatment, dermatology, cancer treatment. Biological applications are also now extended to agriculture and, more recently, to cosmetic. Despite the huge number of in vitro and in vivo experiments there are still numerous challenges to overcome linked to the nature of the encountered target (biological tissues and materials, organs and their direct environment, liquids) that have a direct effect on the produced plasma itself and on the generated species. It is clear that the extremely strong coupling between the characteristics of the plasma and those of the target, as already shown, will play a very important role in the results observed during the treatments. A variation in the chemical or physical characteristics of the target will involve significant differences in the gas flow, the local temperature, or the induced electric field, resulting de facto in variations in the production of the reactive species. It also concerns the transposition of the results between the in vitro and the in vivo experiments that are carried out under extremely different conditions, especially concerning the equivalent electric circuit of the reactor / plasma / biological target assembly. These problems directly affect the identification of the processes involved and currently limit the possibility of a definition of a "dose" in plasma treatments. Recently, study reported led to reflections on non-sustainable tumor response. The loss of effectiveness under long-term plasma treatment of cancer tissue opens questions about plasma application and protocol. It must be considered that the treated area is morphologically and chemically changing over the time, from activated surrounding to more normal tissues that are less humid and bacteriologically cleaner. This aspect is particularly important for the development of efficient systems and protocols in plasma cancer treatment but also for any other plasma therapeutically approaches. It induce a in real-time in situ control of plasma production and at longer term a protocol adaptation taking into account the biological target evolution. Some progress are already done in that domain