Recent advances in molecular biology have elucidated some of the mechanisms that regulate skeletal muscle growth. Logically, muscle physiologists have applied these innovations to the study of resistance exercise (RE), as RE represents the most potent natural stimulus for growth in adult skeletal muscle. However, as this molecular-based line of research progresses to investigations in humans, scientists must appreciate the fundamental principles of RE to effectively design such experiments. Therefore, we present herein an updated paradigm of RE biology that integrates fundamental RE principles with the current knowledge of muscle cellular and molecular signalling. RE invokes a sequential cascade consisting of: (i) muscle activation; (ii) signalling events arising from mechanical deformation of muscle fibres, hormones, and immune/inflammatory responses; (iii) protein synthesis due to increased transcription and translation; and (iv) muscle fibre hypertrophy. In this paradigm, RE is considered an 'upstream' signal that determines specific downstream events. Therefore, manipulation of the acute RE programme variables (i.e. exercise choice, load, volume, rest period lengths, and exercise order) alters the unique 'fingerprint' of the RE stimulus and subsequently modifies the downstream cellular and molecular responses.