Using two different melanoma cell lines and three different methods for FKBP51 modulation, namely short interfering RNA (siRNA), short hairpin RNA (sh-RNA), and CRISPR/Cas9 KO, we show that FKBP51 silencing increased DR5 expression and enhanced sensitivity of melanoma cells to TRAIL-induced apoptosis. The gene discussed is TNFRSF10B; the disease is melanoma.