Extreme weather conditions driven by climate change have resulted in higher average temperatures, more frequent intense heat waves, increased drought conditions, improper soil conditions, as well as increased pest and disease incidence, posing a unique challenge to plants. Until now, several studies have been performed to reveal how plants can acclimatize or cope with these unfavorable conditions. These studies have majorly focused on how plants respond to an individual stress at a particular point in time. But in nature, no stress occurs in isolation; rather, they act mostly in combination. This condition is referred to as "multifactorial stress combination" or, more precisely, it is termed as "stress matrix". The damages and corresponding responses from individual stresses and stress combinations may entirely be different, leading to complex downstream signaling. Through this review, we have made an attempt to decipher the physiological and molecular responses of different plant species to multiple stress combinations. It is further emphasized that more focus needs to be drawn towards the development of plants that are tolerant to multiple or co-occurring stress factors, keeping in mind the adversities of the consistently challenging environmental conditions.