Based on current research, we present a consolidated set of theses which explain the pathomechanisms of vitiligo- and melanoma-associated hypopigmentation. The main thesis is the Double Strike Hypothesis, i.e. vitiligo is caused by at least two different major pathomechanisms: an antibody-based pathomechanism and a T-cell-based pathomechanism. The antibody-based pathomechanism is dominant in diffuse vitiligo, while the T-cell based pathomechanism is dominant in localised vitiligo. Based on this main thesis we derive new therapeutical approaches to vitiligo and melanoma by using the different pathomechanisms. Finally we explain why melanoma-associated hypopigmentation as a natural immunotherapy is still in statu nascendi.