The advent of novel and high-throughput sequencing (next generation) technologies allowed for the sequencing of the genome at an unprecedented depth. The majority of transcribed RNAs have been classified as non-coding RNAs. Among them, long non-coding RNAs (lncRNAs) are emerging as important regulators in many biological processes. Here, we discuss the role of those lncRNAs which are under the control of p53 or that are able to regulate its activity, due to the central role of p53 pathway in many conditions. We also briefly discussed the emerging need of having novel strategies and computational tools to completely unravel the multifaceted roles of lncRNAs and to pave the way to the development of novel diagnostic and therapeutic applications based on these peculiar molecules.