In June, 1849, the cholera raged in Potosi. He was stricken down, and, while violently ill, his wife and infant daughter died of this disease. The following winter he served in the Missouri Legislature, and secured the passage of the bill for the Iron Mountain road. He was subsequently largely concerned in developing and mapping the entire railroad system in that State. In 1851 he removed to St. Louis, and was appointed land agent and attorney for the Pacific railroad. In the year 1853 he was married, the second time, to Pattie B. Scott, eldest daughter of Rev. Robert Scott, deceased, of the Virginia Conference. He was elected in 1858 a member of the Missouri State Senate from the city of St. Louis. In this body he at once took a prominent position, and was a member of nearly every important committee of the body. In the session of 1860-'61 he was chairman of the Committee on Federal Relations, at that time the most important committee of the Senate. He was decidedly conservative in his views, and anxious to secure the preservation of the Union, if it could be done consistently with the rights of the South; but when the Peace Congress proved a failure, the Crittenden Compromise was rejected, and Virginia seceded, he became a secessionist, and was heart and soul with the South throughout the struggle. His position and opinions on the vexed question forced him to leave Missouri. Without hesitation he sacrificed all for his principles, left his family in St. Louis, and joined the forces under General Sterling Price, on whose staff he served for two years as volunteer aid. Being convinced that the many reverses in that department, at that period, were due in a great measure to lack and inferiority of transportation, he called the attention of the authorities at Richmond to this point. He was soon after authorized to establish the Confederate Transportation Works at Columbus, Ga. To this important interest he directed his whole energies, and succeeded in establishing one of the best arranged, most extensive and complete machine shops in the Confederacy. This position he retained until the close of the War, when he removed with his family to Montgomery, Ala., and returned to the practice of law. While there he was elected to the Presidency of Randolph-Macon College. On reaching Virginia and entering upon his duties he found great difficulties in his path. But with characteristic energy he at once addressed himself to the task of re-establishing the College. Nearly two years of unremitted toil, under the most discouraging circumstances, convinced him that success could never crown his efforts at that location. He felt that to make the College a success it must be removed to a more accessible point. Fortunately, just at this juncture of affairs, the hotel property at Ashland was thrown upon the market. With his quick foresight, Colonel Johnson realized the importance of securing this eligible location.