Starting from 1900, Drosophila melanogaster has been studied in the laboratory by scientists interested in many different aspects of animal development, physiology, and evolution. Over much of this more than hundred year period, genetic analyses have been at the basis of most studies, also those who led to the Nobel prices attributed to scientists working with Drosophila. More recently, fluorescent proteins and optogenetic tools have been added to the ever-expanding genetic toolbox allowing for a better understanding of basic cellular processes underlying complex developmental processes.

Even more recently, a novel approach is being added to the toolbox. Small protein binders can be used to directly target and manipulate proteins in their native environment, in cells of the living organism. The development of numerous antibody- and non-antibody-based scaffolds of protein binders (Fig. 1) has allowed the rapid identification of such small binding domain, recognizing virtually any target protein of interest. Such binding molecules can then be functionalized in many different ways, allowing for acute and direct protein manipulation in vivo (degradation, trapping, relocalization, etc.; Fig. 2). Several cases in which such small, functionalized protein binders have been used in Drosophila will be discussed, and a look into the promising future of research with Drosophila will end the presentation.