Purpose of Review <p>Cancer remains a major global health concern, ranking as the second leading cause of death worldwide. Within the tumor microenvironment proteases play a crucial role in cancer cell migration and progression. Their involvement in processes from tumor growth to metastasis has spurred extensive research into their therapeutic potential. This review explores the role of proteases in tumor biology and evaluates their therapeutic targeting through protease inhibitors.</p> Recent Findings <p>Proteases, ranging from metalloproteases to cysteine proteases, play pivotal roles in extracellular matrix degradation, angiogenesis, and the maintenance of cancer stem cell niches. Their involvement in cancer pathogenesis has led to development of protease inhibitors as potential anti-cancer agents, with matrix metalloprotease inhibitors (MMPIs) showing significance due to their enzymatic activity. The source for the development of these inhibitors may be derived either naturally or may be synthesized artificially based on principles of protein structure, peptide bonding, and molecular interactions. Additionally, drugs targeting protein pathways either directly or through epigenetic regulation have demonstrated therapeutic potential. Advancements in nanotechnology now offer promising drug delivery systems with reduced side effects compared to traditional methods.</p> Summary <p>Targeting proteases represents a multidimensional approach to cancer therapy. Though challenges remain, protease inhibitors present a multifaceted approach to cancer treatment, holding the potential to transform the landscape of cancer therapeutics.</p>