This paper presents a new generation of parton distribution functions (PDFs) with increased precision and quantitative estimates of uncertainties. The work significantly extends previous CTEQ and other global analyses by fully incorporating available experimental correlated systematic errors and systematically treating the uncertainties of PDFs and their physical predictions using an eigenvector-basis approach to the Hessian method. The new gluon distribution is significantly harder than previous standard fits, and the uncertainties on various physics issues, particularly the behavior of the gluon distribution, are addressed in more quantitative terms. Extensive results on the uncertainties of PDFs at various scales and on parton luminosity functions at the Tevatron RunII and the LHC are presented, providing means to estimate the uncertainties of a wide range of physical processes at these high-energy hadron colliders. The uncertainties on the production cross sections of $W$, $Z$ at the Tevatron and the LHC are estimated to be $\pm 4\%$ and $\pm 5\%$ respectively, and those for a light Higgs at the LHC to be $\pm 5\%$. The paper also discusses the progress made in global QCD analysis, the impact of higher-twist terms, and the potential for observing signals of new physics at the Tevatron and the LHC.This paper presents a new generation of parton distribution functions (PDFs) with increased precision and quantitative estimates of uncertainties. The work significantly extends previous CTEQ and other global analyses by fully incorporating available experimental correlated systematic errors and systematically treating the uncertainties of PDFs and their physical predictions using an eigenvector-basis approach to the Hessian method. The new gluon distribution is significantly harder than previous standard fits, and the uncertainties on various physics issues, particularly the behavior of the gluon distribution, are addressed in more quantitative terms. Extensive results on the uncertainties of PDFs at various scales and on parton luminosity functions at the Tevatron RunII and the LHC are presented, providing means to estimate the uncertainties of a wide range of physical processes at these high-energy hadron colliders. The uncertainties on the production cross sections of $W$, $Z$ at the Tevatron and the LHC are estimated to be $\pm 4\%$ and $\pm 5\%$ respectively, and those for a light Higgs at the LHC to be $\pm 5\%$. The paper also discusses the progress made in global QCD analysis, the impact of higher-twist terms, and the potential for observing signals of new physics at the Tevatron and the LHC.