The development of less calcemic vitamin D analogs creates possible therapeutic applications for immune modulation (e.g., autoimmune diseases and graft rejection), inhibition of cell proliferation and induction of cell differentiation (e.g., cancer). Recently more insight was obtained in the mechanism of action of the analogs at the biological and molecular level. Critical remarks are summarized on why the step towards the clinic has not yet been taken and how better selective vitamin D receptor modulators could be designed.