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Graphical abstract Figure. No caption available. ABSTRACT We address, for the first time, the impact of skin insertion on multiple occasions of polymeric microneedle arrays in an animal model in vivo. Dissolving microneedle arrays prepared from aqueous blends of 20% w/w Gantrez® S‐97 BF and 40% w/w poly(vinyl pyrrolidone) 58 kDa and hydrogel‐forming microneedle arrays prepared from aqueous blends of and poly(ethyleneglycol) 10 kDa were repeatedly applied to the skin of hairless mice in vivo. Skin appearance and skin barrier function, as illustrated by measurement of transepidermal water loss, were not measurably altered during the entire study period. Biomarkers of infection, immunity and inflammation/irritation were also statistically unchanged, regardless of the microneedle formulation, needle density or number of applications. Mice remained healthy throughout and continued to gain weight during the study. For example, transepidermal water loss values were typically in the range 10–15 g m−2 h−1 immediately prior to microneedle insertion and 15–25 g m−2 h−1 immediately following microneedle removal, regardless of when they were measured during the study periods. Serum biomarker levels, measured immediately post‐mortem were always in the range 10–20 &mgr;g ml−1 for C‐reactive protein, 0.5–1.5 mg ml−1 for Immunoglobulin G and 1000–2500 pg ml−1 for interleukin 1‐&bgr; and were never statistically different from untreated controls. No measurable levels of tumour necrosis factor‐&agr; were found in any animals. These findings are encouraging for the formulations investigated, suggesting that their repeated use by patients will not cause undesirable side‐effects. By beginning to address potential regulatory questions at an early stage, the microneedles field will be ideally‐placed to take advantage of the potential market. This work illustrates a potential pre‐clinical strategy for development of regulatory dossiers on microneedle technologies.