Human naïve embryonic stem (HNES) cells can self-renew under defined culture conditions and closely resemble the preimplantation epiblast lineage. Whilst some of the signalling cascades that are fundamentally implicated in modulating the naïve gene regulatory network have been studied, our understanding of the finer details is incomplete. To date, the roles of the WNT signalling cascade remains a topic of controversial debate. To explore how WNT signalling interacts with other signalling cascades to regulate the maintenance and differentiation of HNES cells, I performed a high throughput, multiparametric hypothesis-driven cell signalling screen. I determined that elevated WNT signalling using CHIR destabilises the naïve pluripotent state and induces hypoblast-like cell differentiation. The inhibitory effects of XAV939 (a potent TNKs inhibitor) act in a WNT-independent manner, determined by the emergence of GATA6 cells in either IWP-L6 or DKK1(two inhibitors of WNT signalling). WNT signalling governs hypoblast- but not trophoblast-like cell differentiation in HNES cells. The blockade of FGF receptors using potent inhibitors derails differentiation and in combination with LIF can facilitate the chemical resetting of primed ES cells to a naïve-like state, however, it cannot sustain long term self-renewal. I established that hypoblast-like cell differentiation hinges upon active WNT/β-Catenin signalling, confirmed when HNES cells were treated with recombinant WNT3A protein and LIF. It is likely that hypoblast genes are co-regulated by NODAL, FGF and LIF signalling and inhibiting any of these pathways perturbs differentiation. Moreover, blocking NODAL signalling in nascent hypoblast-like cell cultures induces AFP expression, resembling visceral-endoderm-like cells. Finally, I examined the expression of the TCF/LEF transcription factors in human pluripotent and differentiated cells. Human naïve ES cells fail to express any of these factors but primed ES cells readily express TCF7L1 and TCF7L2. Trophoblast-like cells robustly express TCF7L2 and hypoblast-like cells express LEF1. Interestingly, NANOG-positive cells in hypoblast-like cell cultures feature TCF7 expression, suggesting that it might be a target of active WNT/β-Catenin signalling, acting in a positive feedforward regulatory loop to activate hypoblast genes such as GATA6 and GATA4. Taken together, these findings highlight clear context-dependent roles for WNT signalling which deserve further investigation in both human pluripotent stem cells and preimplantation embryos. I hypothesise that contrary to present viewpoints regarding WNT/β-Catenin signalling in human naïve pluripotency, activation of this pathway at a physiological level (Takashima et al., 2014; Guo et al., 2017) is advantageous rather than being inhibitory to their self-renewal. This is due to significant changes in the transcription factor network (a lack of KLF2, ESRRB and TCF7L1) and a repurposing of the signalling cascades (a higher requirement for NODAL signalling and is its expression is dampened by TCF7L1).