New Findings What is the central question of this study? Do changes in myofibre cross-sectional area, pennation angle and fascicle length predict vastus lateralis whole-muscle cross-sectional area changes following resistance training? What is the main finding and its importance? Changes in vastus lateralis mean myofibre cross-sectional area, fascicle length and pennation angle following a period of resistance training did not collectively predict changes in whole-muscle cross-sectional area. Despite the limited sample size in this study, these data reiterate that it remains difficult to generalize the morphological adaptations that predominantly drive tissue-level vastus lateralis muscle hypertrophy. Myofibre hypertrophy during resistance training (RT) poorly associates with tissue-level surrogates of hypertrophy. However, it is underappreciated that, in pennate muscle, changes in myofibre cross-sectional area (fCSA), fascicle length (L-f) and pennation angle (PA) likely coordinate changes in whole-muscle cross-sectional area (mCSA). Therefore, we determined if changes in fCSA, PA and L-f predicted vastus lateralis (VL) mCSA changes following RT. Thirteen untrained college-aged males (23 +/- 4 years old, 25.4 +/- 5.2 kg/m(2)) completed 7 weeks of full-body RT (twice weekly). Right leg VL ultrasound images and biopsies were obtained prior to (PRE) and 72 h following (POST) the last training bout. Regression was used to assess if training-induced changes in mean fCSA, PA and L-f predicted VL mCSA changes. Correlations were also performed between PRE-to-POST changes in obtained variables. Mean fCSA (+18%), PA (+8%) and mCSA (+22%) increased following RT (P < 0.05), but not L-f (0.1%, P = 0.772). Changes in fCSA, L-f and PA did not collectively predict changes in mCSA (R-2= 0.282, adjusted R-2 = 0.013, F-3,F-8 = 1.050, P = 0.422). Moderate negative correlations existed for percentage changes in PA and L-f (r = -0.548, P = 0.052) and changes in fCSA and L-f (r = -0.649, P = 0.022), and all other associations were weak (|r| < 0.500). Although increases in mean fCSA, PA and VL mCSA were observed, inter-individual responses for each variable and limitations for each technique make it difficult to generalize the morphological adaptations that predominantly drive tissue-level VL muscle hypertrophy. However, the small subject pool is a significant limitation, and more research in this area is needed.