The world is experiencing new relations between natural, synthetic, and digital substances. Rather than considering these as materially distinct or ontologically separate, this special issue of TSANTSA interrogates how they are interlocked in socio-material processes of mediation, transmutation, and valuation. By conceptualizing the specificity of their separateness, the special issue makes possible the comparison and commensuration of their relationship, and to move beyond their essential qualities. What are the boundaries, leakages, or dis/connections between human and digital, natural and artificial, the organic and synthetic matters? Based on ethnographic research in laboratories, gold refineries, bio-tech microbial seeds and digitally-produced natural sounds, human-machine apps and cellular agriculture, each contribution theorizes the mediation, transmutation, and valuation of natural synthetics, the humanness of artificial intelligence, or the materiality of digital elements.