Differential expression of long non-coding RNAs (lncRNAs) during differentiation and their misregulation in cancer highlight their potential as cell fate regulators. While some example lncRNAs have been characterized in great detail, the functional in vivo relevance of others has been called into question. Finding functional lncRNAs will most probably require a combination of complementary approaches that will greatly vary depending on their mode of action. In this review, we discuss the different tools available to dissect genetically lncRNA requirements and how each is best suited to studies in particular contexts. Moreover, we review different strategies used to select candidate lncRNAs and give an overview of lncRNAs described to regulate development and cancer through different mechanisms.