O2-dependent heme enzymes such as oxidases and oxygenases play important roles in numerous biological processes and much progress has been made in understanding structural features responsible for their diverse and efficient functions. An ultimate test of our knowledge in this area is to apply the insights gained from the study of native enzymes and their variants to design and engineer novel heme enzymes with similar O2-dependent catalytic activity. This endeavor will not only enrich our knowledge further, but also result in artificial catalysts for biomedical applications. In this chapter, we will highlight recent progress made in the design and engineering of structural and functional models of heme-containing monooxygenases, dioxygenases, and oxidases by redesigning native enzymes or by de novo design of new enzymes. In addition, heme-containing DNA or RNA enzymes with oxidase activity are also described. Finally, insights gained from these studies and perspectives for future directions are also summarized.