The short lifetime and thereby the diffusion length of singlet oxygen as well as the correlation between photosensitizer (PS) fluorescence and treatment effects made it attractive in the 80-ties to analyze the intracellular localization of PSs to reveal the initial intracellular hit in PDT. Some PSs were found intracellularly in fluorescing granules that was found to be lysosomes and endosomes. Such vesicles were rupture upon exposure of the cells to light and the PS relocated to other compartments in the cells. About 40 different hydrolytic enzymes are found in late endosomes and lysosomes. Release of lysosomal hydrolases into cytosol has been documented to be a cytotoxic event. This suicide sac hypothesis suggests that released hydrolases lead to impairment of the cells and the cells subsequently die. However, it was found that a large fraction of the vesicles containing PSs could be ruptured without inducing substantial cytotoxicity. The scientific basis for this surprising observation as well as the potential utilization of the photochemical rupture of endosomes and lysosomes for intracellular delivery of various therapeutics, named photochemical internalization (PCI), will be discussed. The PCI technology may be utilized for delivery of all type of molecules accumulating in endocytic vesicles as documented for peptides, protein, oligonucleotides (siRNA and PNA), genes delived by polycationic vectors, adenoviral and adenoassociated vector, for improved antigen presentation for cancer vaccination as well as some small molecular drugs such as bleomycin. Outcome of some clinical trials will also be presented. During the last 20-30 years macromolecular therapeutics have become increasingly attractive for treatment of cancer due to their improved specificity and reduced side effects. Intracellular delivery of macromolecular therapeutics has however so far showed only limited success, a limitation that may be circumvented by PCI. The historic and scientific basis for PCI will be presented.