Progressive research in the past decade converges to the impact of PHLPP in regulating the cellular metabolism through PI3K/AKT inhibition. Aberrations in PKB/AKT signaling coordinates with impaired insulin secretion and insulin resistance, identified during T2D, obesity and cardiovascular disorders which brings in the relevance of PHLPPs in the metabolic paradigm. In this review, we discuss the impact of PHLPP isoforms in insulin signaling and its associated cellular events including mitochondrial dysfunction, DNA damage, autophagy and cell death. The article highlights the plausible molecular targets that share the role during insulin-resistant states, whose understanding can be extended into treatment responses to facilitate targeted drug discovery for T2D and allied metabolic syndromes.