Propeptides of cysteine proteases including papain and cathepsins B, K, L, and S are selective inhibitors of their cognate cysteine proteases. A new class of endogenous inhibitors homologous to the propeptide regions of cysteine proteases has been identified and characterized in the past few decades. These include the mouse cytotoxic T-lymphocyte antigen-2 (CTLA-2), Bombyx cysteine proteinase inhibitor (BCPI), Drosophila crammer, and salmon salarin. They have been categorized as I29 (CTLA family) in the MEROPS peptidase database. In this review, we summarized experimental findings on their molecular forms, inhibition mechanisms, and biological functions. The overall properties of these inhibitors, molecular structures and inhibition mechanisms were found to be similar to those of propeptides of cysteine proteases. CTLA-2 has been shown to possess a unique inhibition mechanism by blocking its cognate enzyme, cathepsin L, through oxidizing the active thiol residue of the enzyme with its own thiol residue. The divergent biological functions of these inhibitors have been determined based on their inhibitory activities towards cathepsin L-like cysteine proteases. CTLA-2 is strongly expressed in the placenta, and may play roles in implantation and decidualization. It is also an inducer of Treg cells in the eyes, and has been shown to induce apoptosis in murine T-lymphoma cells and cardiac fibroblasts. In the brain, CTLA-2 transcript is strongly expressed in neuronal cell bodies while the protein is localized in dendrites and fibre bundles. BCPI has been demonstrated to exhibit anti-parasitic activity and thus thought to act as a negative regulator of silk gland histolysis. Crammer has been identified in mushroom bodies (brain) of Drosophila melanogaster as one of the proteins essential for long-term memory formation through regulation of cathepsin activity in the insect. These findings suggest that the inhibitors are novel proteins that participate in various physiological actions in different organisms. Their emerging roles in normal biological tissues, diseases and as potential targets for drug development are discussed in detail.