Subcellular organellar contact sites, particularly those between mitochondria and the endoplasmic reticulum (MERCSs), play crucial roles in maintaining health. These specialized partitions facilitate vital communication between the organelles, regulating processes essential for cell function, including calcium balance, lipid biogenesis and transport, mitochondrial dynamics, and programmed cell death. Growing evidence shows that perturbation of MERCSs contributes significantly to various diseases, including neurodegenerative disorders like Alzheimer’s and Parkinson’s, metabolic issues, such as type 2 diabetes, heart conditions, and cancer. This review dives into this expanding field, exploring MERCSs as potential therapeutic targets. It provides a detailed overview of the proteins and processes that form and maintain MERCSs, highlighting how their disruption can lead to cellular dysfunction and disease. Additionally, it examines recent exciting breakthroughs in developing drugs and strategies that can manipulate MERCSs for clinical benefits. While challenges remain, this review emphasises the potential of MERCS-based therapies and outlines the critical research needed to move these treatments from the lab to the clinic.