Objective: To comparatively analyze the difference in the expression of 54 transcription factors in the hypothalamus using protein chips following the medication of Chinese drugs for Shen (肾)-tonification, Herba Epimedii, and Fructus Ligustri lucidi (FL) to aged rats. Methods: Wistar rats, aged 15 months of SPF grade, were randomized into three groups, three males and three females in each group. They were medicated with Herba Epimedii decoction (HED, 0.14 g/kg), Fructus Ligustri lucidi decoction (FLD, 0.12 g/kg), and distilled water, respectively, twice a day for 15 days. The rats were sacrificed at the morning of the 16th day 1 h after medication, and their hypothalamus was taken and made into homogenate under an ice-bath for detecting the expression of transcription factors with chip technique. Results: The expressions of signal transduction and transcription activation factor-6 (Stat-6) and androgen receptor (AR) were up-regulated, and those of pre-B transcription factor1 (Pbx-1), stat-1 and AP-2 were down-regulated in both HED and FLD treated groups, but these changes occurred mainly in female rats in the former while mainly in males in the latter. Conclusions: Chinese drugs for Shen-tonification could impact the expression of transcription factors in the hypothalamus of aged rats, dominantly on the neuro-endocrine factors responsible for the growth and development. The effects of drugs for tonifying Shen-yang and for tonifying Shen-yin are different, which is probably one of the pharmacological mechanisms of the Shen-tonifying drugs.