Stem cell fate depends on surrounding microenvironment, the so called niche. For this reason, understanding stem cell niche is one of the most challenging target in cell biology field and need to be unraveled with in vivo studies. Planarians offer this unique opportunity, as their stem cells, the neoblasts, are abundant, highly characterized and genetically modifiable by RNA interference in alive animals. However, despite impressive advances have been done in the understanding planarian stem cells and regeneration, only a few information is available in defining signals from differentiated tissues, which affect neoblast stemness and fate. Here, we review on molecular factors that have been found activated in differentiated tissues and directly or indirectly affect neoblast behavior, and we suggest future directions for unravelling this challenge in understanding planarian stem cells.