The recent outbreak of Zika virus (ZIKV) infection has caused global concern due to its link to severe damage to the brain development of foetuses and neuronal complications in adult patients. A worldwide research effort has been undertaken to identify effective and safe treatment and vaccination options. Among the proposed viral and host components, the viral NS2B-NS3 protease represents an attractive drug target due to its essential role in the virus life cycle. Here, we outline recent progress in studies on the Zika protease. Biochemical, biophysical, and structural studies on different protease constructs provide new insight into the structure and activity of the protease. The unlinked construct displays higher enzymatic activity and better mimics the native state of the enzyme and therefore is better suited for drug discovery. Furthermore, the structure of the free enzyme adopts a closed conformation and a preformed active site. The availability of a lead fragment hit and peptide inhibitors, as well as the attainability of soakable crystals, suggest that the unlinked construct is a promising tool for drug discovery. As an attractive antiviral drug target, the two-component NS2B-NS3 protease from Zika virus has been subjected to intensive structural and functional studies for the identification and characterization of specific inhibitors. The unlinked protease resembles the native state of the enzyme and has higher protease activity than the covalently linked NS2B-NS3 via a glycine-rich peptide linker. The unlinked protease adopts a closed conformation in which the NS2B cofactor is fully engaged with the NS3 protease. An empty substrate-binding site is preformed; it does not undergo further significant conformational changes upon inhibitor binding. The linked protease can assume both open and closed conformations in solution. Several protease–inhibitor complexes are now available. These new findings could guide the future study of the proteases from related flaviviruses.