Two proteins have recently received considerable attention in the neurodegenerative research field: TDP-43 and FUS/TLS. The reason is that both proteins have been found to represent major protein components of the intracellular inclusions occurring in the neuronal tissues of patients affected by Fronto Temporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. One of the most interesting features of this discovery is that both proteins have in common several structural properties. In particular, they are multifunctional RNA-binding proteins (RBPs) already known to play a role in several cellular processes such as transcription, pre-mRNA splicing, and mRNA stability. The potential consequences of changes in their intracellular localization and protein modification status (phosphorylation, ubiquitination, and cleavage) on neuronal metabolism represent one of the major research challenges faced today by researchers. There is hope that a detailed knowledge of the gain- or loss-of-function mechanisms mediated by alterations in these proteins in the neuronal environment may provide novel therapeutic strategies for the treatment of these diseases. Here, we aim to provide an updated review of ways by which TDP-43 and FUS/TLS influence gene expression. In particular, we will focus on the characterized properties of both proteins that involve gene transcription and also RNA splicing, transport and stability processes.