Resistance Exercise (RE) is a widely practiced activity both in leisure time and in training periods for competitive athletes. Recent advanced in molecular biology and muscle physiology has elucidated some of the mechanisms that regulate muscle growth. However, these molecular advances require application in acute program variables of RE. Therefore, we present an updated paradigm of resistance exercise variables and the effect manipulating these has on signalling pathways and hormonal response to optimise RE adaptations. We herein explore the effect of altering (i) choice of exercise; (ii) order of exercises performed; (iii) load (weight/resistance); (iv) volume (i.e. repetitions x sets x load) and (v) rest period between sets. Manipulating these variables has a consequential effect on signalling pathways, hormone response and neural adaptations that may influence protein synthesis and therefore gradual protein accretion leading to increased muscle size and strength.