Twenty-first century and global skills are generally described as competencies for communication and problem solving. Additionally, these skills involve developing the ability to view content-specific issues through a multicultural perspective. Preparing K-12 students for STEM careers in an ever-changing workplace means they must have opportunities to concurrently acquire skills in twenty-first century and global learning. Additionally, the professional biology community has called for advancing middle grades students' knowledge of complex scientific phenomena using novel pedagogies like Project-Based Learning (PBL). Thus, middle grade educators are now tasked to design classroom opportunities for STEM-focused PBL using global interaction to hone global and twenty-first century skills, while developing students' content knowledge. In this article, we provide an account of a classroom-centered project that paired middle school students in Texas with Chinese peers to collaborate on a biology-based PBL activity on the topic of genetics. During the seven-day unit on heredity, the goal was to utilize global collaboration in STEM to achieve learning objectives in the biology curriculum (understanding inheritance and differentiating between dominant and recessive traits), while embedding skills that foster global competency and twenty-first century skills. The context, planning, and outcomes of the global collaboration are discussed, as well as recommendations for future global collaborative STEM initiatives in middle school.