The somatic component of follicular structure is a mixture of different cell types, represented by Granulosa cells (GCs) that are the paracrine regulators of the oocyte growth. GCs finely support this process by a continuous bidirectional talk with oocyte, which ensure oocyte quality and competence. Specific pathways are involved in the cross-talk and in both GCs and oocyte development. This review summarizes data from GCs gene expression analysis concerning both their physiological role and their interaction with oocyte. We also explore the CGs transcriptome modifications induced by controlled ovarian stimulation (COS) or pathological conditions and their impact in reproduction. The transcriptome analysis of GCs could be a powerful tool to improve our knowledge about the pathways involved in oocyte development. This approach, associated with new technologies as RNA-seq could allow the identifications of new noninvasive biological markers of oocyte quality to increase the efficiency of clinical IVF. Moreover, GCs expression analysis could be useful to shed light on new therapeutic targets by providing new options for the treatment of infertility.