Proteolysis is the primary mechanism used by all cells not only to dispose of unwanted proteins but also to regulate protein function and maintain cellular homeostasis. Proteases that reside in the endocytic pathway are the principal actors of terminal protein degradation. The proteases contained in the endocytic pathway are classified into four major groups based on the active-site amino acid used by the enzyme to hydrolyze amide bonds of proteins: cysteine, aspartyl, serine, and metalloproteases. The presentation of peptide antigens by major histocompatibility complex (MHC) class II molecules is strictly dependent on the action of proteases. Class II molecules scour the endocytic pathway for antigenic peptides to bind and present at the cell surface for recognition by CD4+ T cells. The specialized cell types that support antigen presentation by class II molecules are commonly referred to as professional antigen presenting cells (APCs), which include bone marrow-derived B lymphocytes, dendritic cells (DCs), and macrophages. In addition, the expression of certain endocytic proteases is regulated either at the level of gene transcription or enzyme maturation and their activity is controlled by the presence of endogenous protease inhibitors.