Vegetable production is a key determinant of contribution from the agricultural sector toward national Gross Domestic Product in a country like India, the second largest producer of fresh vegetables in the world. This calls for a careful scrutiny of the threats to vegetable farming in the event of climate extremes, environmental degradation and incidence of plant pests/diseases. Cucurbits are a vast group of vegetables grown almost throughout the world, which contribute to the daily diet on a global scale. Increasing food supply to cater to the ever-increasing world population, calls for intensive, off-season and year-round cultivation of cucurbits. Current situation predisposes these crops to a multitude of stressors, often simultaneously, under field conditions. This scenario warrants a systematic understanding of the different stress specific traits/mechanisms/pathways and their crosstalk that have been examined in cucurbits and identification of gaps and formulation of perspectives on prospective research directions. The careful dissection of plant responses under specific production environments will help in trait identification for genotype selection, germplasm screens to identify superior donors or for direct genetic manipulation by modern tools for crop improvement. Cucurbits exhibit a wide range of acclimatory responses to both biotic and abiotic stresses, among which a few like morphological characters like waxiness of cuticle; primary and secondary metabolic adjustments; membrane thermostability, osmoregulation and, protein and reactive oxygen species homeostasis and turnover contributing to cellular tolerance, appear to be common and involved in cross talk under combinatorial stress exposures. This is assumed to have profound influence in triggering system level acclimation responses that safeguard growth and metabolism. The possible strategies attempted such as grafting initiatives, molecular breeding, novel genetic manipulation avenues like gene editing and ameliorative stress mitigation approaches, have paved way to unravel the prospects for combined stress tolerance. The advent of next generation sequencing technologies and big data management of the omics output generated have added to the mettle of such emanated concepts and ideas. In this review, we attempt to compile the progress made in deciphering the biotic and abiotic stress responses of cucurbits and their associated traits, both individually and in combination.