Low Molecular Weight (LMW) amphiphiles are promising class of chemicals that often enable gelation through formation of supramolecular self-assemblies driven by physical forces such as hydrophobic, hydrogen bonding and π-π interactions. These gels are of prime importance for wide range of biomedical applications like 3D-cell culture, enzyme immobilization, drug delivery, self-healing bandages etc. due to their ease of fabrication, biocompatibility, biodegradability, ease of modification and reversibility. However, low mechanical strength limit the applications of these physical gels. Herein, various strategies that have been adopted over the past two decades to advance the properties of different LMW gels are summarized. Structural modification in urea, saccharides, amino acids, peptides, bile acids and nucleobases induce functionalities in the corresponding gels that demonstrate applications such as injectable drug delivery vehicles, stimuli responsive delivery agent, pollutant adsorbents, catalysts, antimicrobial activity to name a few. The review also emphasizes on the developments in the field of engineered gels such as core-shell, double network and nanocomposite gel scaffolds that emphasizes on a facile modification of LMW gels to yield soft materials with higher toughness and tensile strength to be utilized for biomedical applications. The review also points toward the arenas which lack sufficient investigation and wherein the scope for further development remains.