Lysosomes are ubiquitous organelles that carry out essential household functions. Certain cell types, however, contain lysosome-related organelles with specialized functions. Their specialized functions are usually reflected by specific morphological and compositional features. A number of diseases that develop due to genetic mutations, pathogen exposure or cell transformation are characterized by dysfunctional lysosomes and/or lysosome-related organelles. In this review we highlight adaptations and malfunction of the endosomal/lysosomal system in normal and pathological situations with special focus on MHC class II compartments in antigen presenting cells and melanosomes in pigment cells.