The idea of design informatics as a distinguished discipline is a new one, with little precedence. This paper argues for the importance of a human-centered perspective with respect to the emergence of this newly nascent field of design informatics—a perspective which may be termed Human-Centered Design Informatics (HCDI). The paper proposes four grand challenges that are essential to the foundations of HCDI, specifically (i) understanding the living nature of information, (ii) understanding the relationships between interaction design and information, (iii) understanding how to design for sustainable and engaging social interactions mediated by information technologies, and (iv) understanding the multi-cultural and globalization issues implied by the use of the materials of information technologies in design.