Recent studies indicate that the majority of the genome is transcribed, however only a fraction of this transcription is annotated as what we traditionally know as genes. Much of this is low level pervasive, and often overlapping transcription, for which the transcript structure and function, has not as yet been determined. Novel RNAs (and novel classes of RNAs), are now being identified by groups using next generation sequencing and cDNA libraries that target specific sub-fractions of the transcriptome (based upon size, modifications, localization and protein interactions). We discuss the state of the art as to measuring and identifying these novel RNAs and speculate on whether a universal approach to transcript isoform and expression level measurement is possible in the near future.