The paper explores approaches to forecasting the gross output in the regional system as well as analyzes their main strengths and weaknesses. Special attention is paid to the analysis of using the Cobb-Douglas production function to forecast the priority directions of the economic activity of enterprises in the region. The authors present a methodical approach to forecasting gross output in the region. The approach takes into account the region specificity as well as the main types of economic activity of enterprises in the territory on the basis of multiple regression analysis. Moreover, it determines the priority directions of the economic activity of enterprises using the parameters of the Cobb-Douglas production function as well as simulates the forecast of the dynamics of gross output. According to this approach, the priority directions of economic activity of enterprises in the regional system are the areas, where the attraction of capital and labor resources are formed by the increasing effect on the scale (when the sum of the regression coefficients in the Cobb-Douglas production function exceeds the value of 1). The approach proposed by the author was implemented for the forecasting of the gross output of the Chelyabinsk region up to 2020. The results of this study identify both the main directions of economic activity, which form a significant part of the gross output in the region (manufacturing, trade and production of electricity, gas and water); and the priority directions of economic activity, which form an additional effect in the dynamics of gross output (manufacturing, retail and wholesale trade, agriculture and forestry, hotel and restaurant business). As a result of the regression analysis, I developed a forecast model, which determined the influence of these directions of economic activity of enterprises on the gross output in the region as well as allowed to form an inertial forecast of its dynamics until 2020, taking into account its current growth rates. The comparison of this scenario with the forecast of gross output for the main types of economic activity of enterprises in the region shows that the development of manufacturing, agriculture and forestry, the hotel and restaurant business will provide an additional increase in gross output in the Chelyabinsk region in 2019 by 33 billion rubles, and in 2020 — by 51 billion rubles.