Internalization and trafficking of cell-surface membrane receptors and proteins into subcellular compartments is mediated by specific short-sequence signal motifs, which are usually located within the cytoplasmic domains of these receptor and protein molecules. The signals usually consist of short linear amino acid sequences, which are recognized by adaptor coat proteins along the endocytic and sorting pathways. The complex arrays of signals and recognition proteins ensure the dynamic movement, accurate trafficking, and designated distribution of transmembrane receptors and ligands into intracellular compartments, particularly to the endosomal-lysosomal system. This review summarizes the new information and concepts, integrating them with the current and established views of endocytosis, intracellular trafficking, and sorting of membrane receptors and proteins. Particular emphasis has been given to the functional roles of short-sequence signal motifs responsible for the itinerary and destination of membrane receptors and proteins moving into the subcellular compartments. The specific characteristics and functions of short-sequence motifs, including various tyrosine-based, dileucine-type, and other short-sequence signals in the trafficking and sorting of membrane receptors and membrane proteins are presented and discussed.