•Covers software opportunities for combinatorial engineering and experimental design.•Outlines challenges for equipment interfacing and proposes potential strategies.•Reviews major classes of sequencing technologies and their software needs.•Discusses approaches to fostering integrated software workflows for bio-design. Bio-design automation (BDA) is an emerging field focused on computer-aided design, engineering principles, and automated manufacturing of biological systems. Here we discuss some outstanding challenges for bio-design that can be addressed by developing new tools for combinatorial engineering, equipment interfacing, next-generation sequencing, and workflow integration. These four areas, while not an exhaustive list of those that need to be addressed, could yield advances in bio-design, laboratory automation, and biometrology.